Dissecting Histone Deacetylase 3 in Multiple Disease Conditions: Selective Inhibition as a Promising Therapeutic Strategy
- Nilanjan AdhikariNilanjan AdhikariNatural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, IndiaMore by Nilanjan Adhikari,
- Tarun Jha*Tarun Jha*E-mail: [email protected]Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, IndiaMore by Tarun Jha, and
- Balaram Ghosh*Balaram Ghosh*E-mail: [email protected]Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, IndiaMore by Balaram Ghosh
Copyright © 2021 American Chemical Society
Abstract
The acetylation of histone and non-histone proteins has been implicated in several disease states. Modulation of such epigenetic modifications has therefore made histone deacetylases (HDACs) important drug targets. HDAC3, among various class I HDACs, has been signified as a potentially validated target in multiple diseases, namely, cancer, neurodegenerative diseases, diabetes, obesity, cardiovascular disorders, autoimmune diseases, inflammatory diseases, parasitic infections, and HIV. However, only a handful of HDAC3-selective inhibitors have been reported in spite of continuous efforts in design and development of HDAC3-selective inhibitors. In this Perspective, the roles of HDAC3 in various diseases as well as numerous potent and HDAC3-selective inhibitors have been discussed in detail. It will surely open up a new vista in the discovery of newer, more effective, and more selective HDAC3 inhibitors.
1. Introduction
ARTICLE SECTIONS
1.1. HDAC and Epigenetic Modulations
Epigenetic manipulations, referred to as alterations of genetic expression, are associated with chemical modulations of cytosine residues of DNA as well as histone proteins.(1−3) Epigenetic modifications through alterations by both histone deacetylases (HDACs) and histone acetyltransferases (HATs) regulate numerous genetic expressions.(4,5) HDACs catalyze the deletion of an acetyl group from the acetylated ε-amino lysines of histone proteins (Figure 1).
Figure 1
Figure 1. Lysine deacetylation of histone proteins catalyzed by HDAC.
Subsequently, HDACs are involved in transcription processes as well as chromatin condensation mechanisms.(6) Nevertheless, HDACs modulate numerous signaling pathways and control normal and diseased pathophysiological conditions.(7,8) Therefore, the overexpression of HDACs has been found to alter normal epigenetic mechanisms and to correlate with numerous disease conditions.
1.2. Classification of HDACs
In mammals, based on the phylogenetic analysis of protein sequences, HDACs have been categorized into four different classes, class I, II, III, and IV(9) (Figure 2, Table 1).
Figure 2
Figure 2. Different classes of HDACs.
Table 1. Detailed Classification of HDAC Family Members
| HDAC | |||||||
|---|---|---|---|---|---|---|---|
| class | member | sequence homology | chromosomal location | expression in tissues | catalytic domain (amino acid sequences) | complex | substratea |
| I | HDAC1 | yeast RDP3 deacetylase | 1p34 | ubiquitous | 9–321 | Sin3, NuRD, COREST | histones (H2), p53 (TP53), E2F-1, STAT3 (STAT3), GATA (GATA), AR (AR), pRB (Rb1), MeCP2 (MECP2), MyoD (MYOD), ATM (ATM), DNMT1 (DNMT1), SHP (NR0B2), NF-κB (NFKB1), MEF2 (MEF2) |
| HDAC2 | yeast RDP3 deacetylase | 6q21 | ubiquitous | 9–322 | Sin3, NuRD, COREST | histones (H2), HOP (HOP), GATA2 (GATA2), Bcl-6 (BCL6), STAT3 (STAT3), glucocorticoid receptor (NR3C1), NF-κB (NFKB1), pRb (Rb1), BRCA1 (BRCA1) | |
| HDAC3 | yeast RDP3 deacetylase | 5q31 | ubiquitous | 3–316 | NCOR/SMRT, NCOR1/NCOR2, GPS2-TBL1X | STAT3 (STAT3), GATA1 (GATA1), RelA (Rela), YY-1 (YY1), MEF2D (MEF2D), SHP (NR0B2), histones (H2), pRb (Rb1), NF-κB (NFKB1) | |
| HDAC8 | yeast RDP3 deacetylase | Xq13 | ubiquitous | 14–324 | EST1B | SMC3 (SMC3), HSP70 (HSP70) | |
| IIa | HDAC4 | yeast HDA1 deacetylase | q37.2 | smooth muscle, heart, brain | 655–1084 | NCOR1/NCOR2, ANKRA, RFXANR | histones (H2), GATA1 (GATA1), GCMa (GCM1), p53 (TP53), SRF (SRF), p21, Runx2 (RUNX2), HP1 (HP1α), HIF-1α (HIF1A), FOXO (FOXO), SUV39H1 (SUV39H1) |
| HDAC5 | yeast HDA1 deacetylase | 17q21 | smooth muscle, heart, brain | 684–1028 | REA, estrogen receptor | Smad7 (SMAD7), GCMa (GCM1), HP1 (HP1α), MEF2 (MEF2), YY1 (YY1), CaM (CAM), Runx2 (RUNX2) | |
| HDAC7 | yeast HDA1 deacetylase | 12q13.1 | smooth muscle, pancreas placenta, heart | 518–865 | Sin3, NCOR2, Bcl-6, HIF-1α | FLAG1 (flaG1), FLAG2 | |
| HDAC9 | yeast HDA1 deacetylase | p21-p15 | kidney, liver, pancreas, heart | 631–978 | FOX3P | histones (H2), Runx2 (RUNX2), CaM (CAM), HIF-1α (HIF1A), PML (PML), MEF2 (Mef2) | |
| IIb | HDAC6 | Xp11.22-23 | 87–404, 482–800 | RUNX2 | Smad7 (SMAD7), SHP (NR0B2), α-tubulin (TUBA1A), HSP90 (HSP90), Runx2 (RUNX2), cortactin (CTTN) | ||
| HDAC10 | 22q13.31 | 1–323 | NCOR2 | PP1 (PP1), HSP90 (HSP90), LcoR (LCOR) | |||
| IV | HDAC11 | class I and II HDACs | 3p25.2 | 14–326 | histones (H2), Cdt1 (CDT1) | ||
a
The names of the respective genes of these substrate proteins are shown in parentheses.
Class I HDACs (namely, HDAC1, HDAC2, HDAC3, and HDAC8) are expressed in the nucleus and are related to the reduced potassium dependency 3 (Rpd3) gene found in yeast even though HDAC3 shuttles between the nucleus and cytoplasm.(10,11) Class I HDACs are composed of a distinctive deacetylase domain. The HDACs belonging to class II are found in both the nucleus and cytoplasm. They are again grouped in two classes, class IIA and class IIB. These class II HDACs display a structural resemblance to the yeast gene Hda1.(12) HDAC4, HDAC5, HDAC7, and HDAC9 are combined in class IIA. However, two other HDACs, HDAC6 and HDAC10, are combined in class IIB. Along with the deacetylase domain, class IIA HDACs possess an N-terminal domain that includes a distinct myocyte enhancer factor (MEF) binding region.(9,13) However, class IIB HDACs possess a unique C-terminal domain. HDAC6, a class IIB enzyme, possesses a zinc-finger ubiquitin binding domain (ZnF-UBP), whereas HDAC10 contains a leucine-rich domain.(9) The distinct HDAC6 N-terminal domain helps to deacetylate α-tubulin.(14) The class IV HDAC, HDAC11, enzyme is found in both nucleus and cytoplasm.(15) Interestingly, sirtuins (SIRT1–SIRT7) are categorized as class III HDACs. However, their functions are not associated with class I and class II HDACs. Both the class I and class II HDACs are completely Zn2+-ion-dependent, whereas the sirtuins (SIRT1–SIRT7) are NAD+-dependent. Each HDAC displays a high degree of structural homology at the active site because of the presence of a conserved tyrosine residue that takes part in the catalytic mechanism. In mammals, class IIA HDACs possess a histidine instead of the tyrosine residue, which reduces the catalytic activity.(9,13)
1.3. HDAC Inhibitors Modulate Diverse Biological Processes
Due to the activity of HDACs in histone deacetylation and epigenetic modulations, HDACs participate in numerous biological signaling events.(6,7) Apart from maintaining a variety of normal physiological events, HDACs modulate several pathophysiological and disease conditions, namely, cancers, neurodegenerative disorders, inflammatory diseases, metabolic disorders, autoimmune diseases, etc.(5−7) HDAC inhibitors are found to modulate a variety of diverse biological activities and cellular functions, as well as various genetic manipulations related to tumor growth inhibition, apoptosis, cell cycle arrest, cell migration and motility, autophagy, antiangiogenic effects, DNA repair, and mediation of nuclear and inflammatory signaling processes(16−18) (Figure 3, Table 2).
Figure 3
Figure 3. HDAC inhibitors in modulating diverse biological conditions.
Table 2. HDAC Inhibitors Modulating Diverse Biological Processes
| function | role of HDAC inhibitors |
|---|---|
| cell cycle arrest | (a) induction of endogenous CDK inhibitor p21;(19−21) (b) induction of p27 related to CDK inhibitory activity;(17) (c) downregulation of cyclin D and cyclin A genes to decrease CDK activities;(17,22) (d) downregulation of c-myc expression;(23) (e) disruption mitotic spindle assembly and checkpoints(24−26) |
| DNA synthesis | downregulation of thymidylate synthetase and CTP synthase(17) |
| cell migration and motility | (a) upregulation of RECK protein which further downregulates MMP-2, MMP-9 and MMP-14;(17,27) (b) upregulation of TIMP-1 and TIMP-3;(17,28) (c) hyperacetylation of tubulin and subsequent decrease in microtubule dynamics;(29) |
| apoptosis | (a) upregulation of pro-apoptotic proteins (namely, Bid, Bim, Bmf, and Noxa) via p53 acetylation;(30−34) (b) induction of genes related to mitochondrial damage (such as apaf1, cytC, and casp9);(17,35) (c) downregulation of antiapoptotic proteins (namely, Bcl2, BCL-XL, c-FLIP, MCL-1, survivin, and XIAP);(36−39) (d) upregulation of TRAIL, Fas, Fas-L and TNF-α-guided activation of caspases;(17,38−40) (e) downregulation of FLIP and IAP2(38−41) |
| DNA damage | (a) induction of the accumulation of ROS followed by induction of mitochondrial disruption and DNA damage;(42−45) (b) downregulation of the expression of genes for DNA repair proteins, namely, BRCA1, BRCA2, RAD51, and Ku70;(46−50) (c) downregulation of TrX but upregulation of TBP2(51) |
| antiangiogenesis | repression of pro-angiogenic proteins like VEGF, HIF-1α, and CXCR4(17,52−55) |
| immunomodulation | (a) upregulation of the MHC class I and class II proteins and ICAM1;(56,57) (b) reduction of the secretion of pro-inflammatory cytokines, namely, TNFα, IL-1, and IFNγ(58,59) |
| autophagy | induction of caspase-independent autophagic cell death(17,60) |
| other diverse biological activities | (a) hyperacetylation of several transcription factors and proteins, namely, p53,(61) NF-κB,(62) and α-tubulin;(63) (b) inactivation of STAT1,(64) STAT3,(65) and STAT5;(66,67) (c) activation of JNK;(68,69) (d) hyperacetylation of chaperone proteins, such as HSP90;(70,71) (e) reduction of proteasome function;(72,73) (f) disruption of aggresome to degrade misfolded proteins(17,74,75) |
a
CDK, cyclin-dependent kinase; RECK, reversion-inducing cysteine-rich protein with Kazal motifs; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of matrix metalloproteinase; c-FLIP, cellular FLICK-like inhibitory protein; MCL-1, myeloid cell leukemia sequence-1; XIAP, X-linked inhibitor of apoptosis; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; TNF-α, tumor necrosis factor-α; FLIP, Flice inhibitory protein; IAP2, inhibitor of apoptosis 2; ROS, reactive oxygen species; Trx, thioredoxin; TBP2, TrX-binding protein; VEGF, vascular endothelial growth factor; HIF-1α, hypoxia inducible factor-1α; CXCR4, C-X-C chemokine receptor type 4; MHC, major histocompatibility complex; ICAM1, intracellular adhesion molecule-1; IL-1; interleukin-1; IFNγ, interferon-γ; STAT, signal transducer and activator of transcription; JNK, Janus kinase; HSP90, heat shock protein 90.
Depending on the diverse biological activities of HDACs, various HDAC inhibitors have been synthesized. A few of these inhibitors have been marketed for treating particular cancers. However, most of them have been evaluated in various phases of clinical trials(1,5,6,8) (Figure 4). The HDAC inhibitory profile of these compounds is listed in Table 3.
Figure 4
Figure 4. Approved and clinically evaluated HDAC inhibitors.(76−107)
Table 3. Inhibitory Profile of the Approved and Clinical Phase HDAC Inhibitors
| HDAC isoform IC50 (nM) | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| drug | 1 | 2 | 3 | 8 | 4 | 5 | 7 | 9 | 6 | 10 | 11 |
| vorinostat (1)(108) | 75.5 | 362 | 57.4 | 1069 | 15056 | 163 | 12522 | 78.1 | 27.1 | 88.4 | 109 |
| belinostat (2)(108) | 17.6 | 33.3 | 21.1 | 157 | 1236 | 76.3 | 598 | 44.2 | 14.5 | 31.3 | 44.2 |
| panobinostat (3)(108) | 2.5 | 13.2 | 2.1 | 277 | 203 | 7.8 | 531 | 5.7 | 10.5 | 2.3 | 2.7 |
| trichostatin (4)(109) | 5 | 8 | 10 | 200 | 5000 | 2600 | 1400 | 10400 | 0.7 | 40 | 10 |
| abexinostat (5)(110) | 21 | 63 | 148 | 370 | 60 | 48 | 350 | 168 | 12 | 52 | 14 |
| resminostat (6)(111) | 42.5 | 50.1 | 877 | 71.8 | |||||||
| givinostat (7)(110) | 133 | 293 | 136 | 837 | >1000 | 532 | 524 | 512 | 312 | 331 | 287 |
| pracinostat (8)(112) | 49 | 96 | 43 | 140 | 56 | 47 | 137 | 70 | 1008 | 40 | 93 |
| bisthianostat (9)(110) | 4 | 13 | 6 | 17 | >1000 | >1000 | >1000 | >1000 | 2 | 2 | 78 |
| quisinostat (10)(110) | 0.1 | 0.3 | 5 | 4 | 0.6 | 4 | 119 | 32 | 77 | 0.5 | 0.4 |
| ricolinostat (11)(110) | 58 | 48 | 51 | 100 | >1000 | >1000 | >1000 | >1000 | 5 | – | >1000 |
| CUDC-101 (12)(113) | 4.5 | 12.6 | 9.1 | 79.8 | 13.2 | 11.4 | 373 | 67.2 | 5.1 | 26.1 | – |
| tucidinostat (13)(114) | 95 | 160 | 67 | 733 | >30000 | >30000 | >30000 | >30000 | >30000 | 78 | 432 |
| tacedinaline (14)(110) | 900 | 900 | 1200 | >10000 | |||||||
| entinostat (15)(114) | 262 | 306 | 499 | 2700 | >30000 | >30000 | >30000 | >30000 | >30000 | 254 | 649 |
| mocetinostat (16)(115) | 150 | 290 | 1660 | >10000 | >10000 | >10000 | >10000 | >10000 | 590 | ||
| domatinostat (17)(116) | 160 | 370 | 130 | >15000 | >15000 | >15000 | >15000 | >15000 | >15000 | >15000 | >15000 |
| romidepsin (18)(110) | 1 | 1 | 1 | >1000 | 647 | >1000 | >1000 | >1000 | 226 | 1 | 0.3 |
Due to pan-HDAC inhibition, HDAC inhibitors produce a number of unacceptable adverse effects (such as neutropenia, thrombocytopenia, hypokalemia, elevated creatinine and uric acid, dehydration, anorexia, nausea, vomiting, diarrhea, flushing, fatigue, and atrial fibrillation),(117,118) and therefore, only a few have been approved for limited use to treat specific cancers (Figure 4).(5,6,110) Therefore, it is inferred that isoform-selective HDAC inhibition not only may help to get rid of the off-target adverse effects but also may be effective in combating various disease conditions. In view of the selectivity and specificity, HDAC3 has been established to be a promising and attractive target to combat multiple diseases. In our earlier communication, we briefly mentioned the implication of HDAC3 in several disease conditions, but focused extensively on almost all the existing HDAC3 inhibitors including their description and detail structure–activity relationship (SAR) analysis.(5) However, in this Perspective, the details of implication of HDAC3 in various disease conditions, including the signaling pathways, as well as the development of potent HDAC3-selective inhibitors, have been discussed extensively. Though HDAC3 is a validated target and HDAC3 selectivity is crucial to avoid off-target toxicity, a number of potent HDAC3 inhibitors remain untested against other HDACs. Therefore, the HDAC3 selectivity issue still remains untested due to incomplete HDAC inhibitory profiling of these compounds. Despite evaluating the HDAC3 inhibitory potency only, compounds should be evaluated for their HDAC3 selectivity over other HDACs, so that proper lead molecules may be identified for further modification. This may be the major limitation regarding the selectivity toward HDAC3. In spite of these limitations, this Perspective will be able to provide detailed implications of HDAC3 in various disease conditions and may help to design newer HDAC3-selective inhibitors in order to develop newer therapies against various diseases related to HDAC3.
2. Structure of HDAC3
ARTICLE SECTIONS
All class I HDAC enzymes (namely, HDAC1, -2, -3, and -8) exhibit structural resemblance to the yeast RPD3 protein. HDAC1 and HDAC2 were initially identified in human beings and subsequently cloned.(119,120) Later, the identification of HDAC3 via homology modeling revealed that HDAC3 is encoded in a similar manner to RPD3 proteins but possesses quite a dissimilar structure compared to HDAC1 and HDAC2.(121) Other than different organs, it is highly expressed in various parts of the brain, namely, cerebellum, hippocampus, cortex, hypothalamus, striatum, amygdala, neurons, and astrocytes.(122,123)
HDAC3 has been found to form a stable complex with nuclear receptor co-repressor (N-CoR) as well as silencing mediator of retinoic acid thyroid receptor (SMRT).(5,124−128) HDAC3 catalyzes deacetylation and represses transcriptional mechanisms.(125) HDAC3 along with N-CoR/SMRT modulates the repression of several nuclear receptors, including thyroid hormone receptor (TR), retinoid X receptor (RXR), retinoic acid receptor (RAR), peroxisome proliferator-activated receptor (PPAR), DAX1, Rev-Erb, and COUP-TFs.(124) Apart from the nuclear receptors, several transcription factors also bind to the complex to form the inactive state of target genes.(124) During HDAC3 activation, the deacetylation activating domain (DAD) modulates SMRT activity in the nuclear receptor co-repressor (N-CoR) complex.(5,129) DAD has a pair of SANT motifs (SANT1 and SANT2) located at the N-termini of SMRT and N-CoR. The highly conserved SANT2 region acts as an essential part of the histone interacting domain (HID) that is crucial for both HDAC3 binding and activation.(5,124,127) Again, the nonconserved C-terminal region is crucial for the deacetylation and repression of transcription processes. The central part of HDAC3 contains a nuclear export signal (NES) and the C-terminal end is responsible for the localization of protein in the nucleus. Moreover, the N-terminal portion is responsible for forming oligomers.(130)
Watson et al.(131) found that HDAC3 does not form a complex with SMRT–DAD in bacteria but forms a complex with SMRT–DAD in mammalian HEK293 cells. Compared to other class I HDACs (namely, HDAC8 and HDAC2), HDAC3 possesses eight β-sheets encompassed by α-helices. A unique tyrosine residue (solvent-exposed) is found near the active site tunnel. The tyrosine residue is supposed to interact with the substrate to regulate substrate specificity. During complex formation with HDAC3, the N-terminal helix of DAD evolves a structural reorganization and resides along the HDAC3 surface forming numerous intermolecular interactions. The SMRT–DAD complex is found to interact with the HDAC3 N-terminal region, forming helices H1–H2, loop L2, and strand S2. Interestingly, this region of HDAC3 is quite dissimilar to HDAC8. The H1 helix of HDAC3 is distorted and looks like a pseudohelix. Due to this structural difference, it may be considered that HDAC8 becomes active without interacting with any co-repressor. The d-myo-inositol-1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P4] links HDAC3 and DAD (Figure 5). Both HDAC3 and SMRT–DAD form hydrogen bonds with amino acids.(131)
Figure 5
Figure 5. (A) Structure of HDAC3 (PDB 4A69) [A chain, indigo; B chain, yellow; C chain, red; D chain, green; zinc ions are shown as magenta spheres; [Ins(1,4,5,6)P4] is located in the interface of A, B and C chains shown as scaled ball and stick model]. (B) Intermolecular interactions of zinc, acetate and surrounding amino acids at A chain. (C) Intermolecular interactions of zinc, acetate, and surrounding amino acids at B chain.
Due to such interactions, Ins(1,4,5,6)P4 is firmly associated with the complex. Ins(1,4,5,6)P4 is a mandatory precondition for the interaction between HDAC3 and SMRT, and it acts like an “intermolecular glue”.(131) Importantly, all the three components, Ins(1,4,5,6)P4, HDAC3, and SMRT–DAD, are necessary for the activation of HDAC3 enzyme. An acetate molecule forms hydrogen bonds to the catalytic Zn2+ ion as well as His134 and Tyr298 (Figure 5).(131) The binding surfaces of both Ins(1,4,5,6)P4 and DAD are situated on the same side of the HDAC3 active site. Conformational changes in Ins(1,4,5,6)P4 and DAD occur during binding to HDAC3. This phenomenon assists in substrate binding and, subsequently, accelerates the enzymatic activity of HDAC3. Compared to HDAC3, the substrate binding mode at the active site of HDAC8 is not dependent on any complex formation. Importantly, in the case of HDAC3, mutations or alterations in Arg265, as well as loop L1 and L6, cause not only the loss of deacetylation but also the abolishment of interactions with SMRT–DAD. Nevertheless, Ins(1,4,5,6)P4 is also a crucial constituent for HDAC3 activity as suggested by the reconstitution assay in vitro.(131)
2.1. Understanding Isoform Selectivity in Terms of Binding Mode of Interactions between HDAC Inhibitors and HDACs
Because different HDAC inhibitors have different binding modes with different HDACs, the pattern of binding orientations may provide newer ideas to design isoform-selective HDAC inhibitors. For example, some potential HDAC inhibitors such as SK-683 (19, Figure 6), CG-1521 (20, Figure 6), and NVP-LAQ824 (21, Figure 6) along with some well-known clinically evaluated HDAC inhibitors, namely, SAHA (1, Figure 4), TSA (4, Figure 4), and MS-275 (15, Figure 4) were considered for their binding interactions with several HDACs by Wang and co-workers.(132)
Figure 6
Figure 6. Potential HDAC inhibitors used to evaluate the binding pattern and orientation with several HDACs
The molecular docking study of HDAC inhibitors, TSA (4), SK-683 (19), and CG-1521 (20), conducted by Wang et al.(132) demonstrated structural variation among different class I HDACs (Figure 7).
Figure 7
Figure 7. Structures of docked TSA (4, green), SK-683 (19, purple), and CG-1521 (20, cyan) in the active sites of HDAC1 (a), HDAC2 (b), HDAC3 (c), and HDAC8 (d) (left) and their top views in these proteins with surface representations (right). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.
The similar binding pattern of trichostatin A (TSA, 4) into all class I HDACs suggests its nonselective behavior (Figure 7a). The docked conformation of TSA (4) also displays a similar binding orientation as in the X-ray cocrystal structure of HDLP–TSA. The hydroxamate zinc binding group (ZBG) of TSA (4) binds to the catalytic Zn2+ ion at the bottom of the 11 Å channel, whereas the associated long aliphatic chain lies in the 11 Å channel. However, the aromatic cap group is located close to Glu98 (HDAC1), Glu99 (HDAC2), or Asp92 (HDAC3).(132) Again, the binding of SK-683 (19) with HDAC1 is found to be different from the binding with HDAC2 and HDAC3. The orientation of two aromatic groups of SK-683 (19) is slightly shifted for HDAC2 and HDAC3 compared to the respective orientation in HDAC1 (Figure 7b).(132) On the other hand, CG-1521 (20) binds close to the 11 Å channel, but the rigid aromatic portion is oriented differently for all HDACs compared to the binding orientation of SAHA (1) and SK-683 (19) (Figure 7c).(132) Apart from HDAC3, TSA (4) is found to bind more strongly with HDAC1 and HDAC2 compared to the other compounds.
On the other hand, the binding energy suggests that SAHA (1) binds to HDAC1, HDAC3, and HDAC8 in a similar orientation, but it is a weaker inhibitor than TSA (4) (Figure 8a).(132)
Figure 8
Figure 8. Structures of docked SAHA (1, blue), MS-275 (15, red), and NVP-LAQ824 (21, yellow) in the active sites of HDAC1 (a), HDAC3 (b), and HDAC8 (c). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.
Interestingly, the similar values of binding energies of SAHA (1) with HDAC1, HDAC3, and HDAC8 also reveal it to be a nonselective one. In the case of MS-275 (15), the close binding interaction energies as well as the similar patterns of binding with both HDAC1 and HDAC3 suggest that it is a dual inhibitor of HDAC1/3. Interestingly, the binding of MS-275 (15) with HDAC8 is completely different compared to binding with HDAC1 and HDAC3 (Figure 8b).(132) It does not bind to the active site of HDAC8 but binds into another cavity. This suggests the presence of a second binding site in HDAC8, and MS-275 (15) is a weak inhibitor of HDAC8. Inhibitor NVP-LAQ824 (21) binds more strongly to HDAC3 compared to HDAC1 and HDAC8. The binding orientation with HDAC3 is also completely different compared to the corresponding binding with HDAC1 and HDAC8 (Figure 8c).(132) Due to the minute change at the binding pocket (Glu98 in HDAC1 vs Asp92 in HDAC3), the orientation of the indolyl cap group of NVP-LAQ824 (21) becomes different. This makes the compound bind strongly at the active site of HDAC3.(132) Such structural differences as well as different binding interactions along with spatial orientations might be helpful in designing isoform-selective HDAC3 inhibitors.
3. HDAC3 in Multiple Disease Conditions
ARTICLE SECTIONS
HDAC3 is a vital HDAC from class I that has been found to play crucial roles in a variety of disease conditions (Figure 9).
Figure 9
Figure 9. Role of HDAC3 in various disease conditions.
HDAC3 plays essential roles in modulating several diseases, such as cancers,(133−136) inflammatory disease conditions,(137) metabolic disorders, interstitial fibrosis, autoimmune disorders (such as rheumatoid arthritis),(138) neurodegenerative and CNS disorders [namely, schizophrenia,(139) spinal cord injury,(140,141) learning and memory dysfunction,(3,142) amyotrophic lateral sclerosis (ALS),(143) major depressive disorder (MDD),(144) spinocerebellar ataxia,(122,145) Parkinson’s disease (PD),(146) Huntington’s disease (HD),(122,147,148) and Alzheimer’s disease (AD)(149,150)], cardiovascular diseases and hypertension,(151−153) diabetes,(154−156) parasitic infections (namely, taxoplasmosis)(157,158) and HIV.(159−161) Therefore, designing potential HDAC3 inhibitors should be an essential and intended criterion for accelerating the drug discovery processes against the above-mentioned diseases in the near future.
3.1. HDAC3 in Cancer
Various studies report diverse functions of HDAC3 in different cancers. HDAC3, an epigenetic modulator in DNA damage and repair, maintains chromatin structure and genome stability.(129,162−164) HDAC3 takes part crucially in histone deacetylation, DNA damage, DNA double strand break repair, and apoptosis.(129,162) It is found to be frequently overexpressed in various cancers, including chronic lymphocytic leukemia, gastric and liver cancer, breast cancer, and renal and colon cancers.(5,165) It was noted that downregulation of HDAC3 decreases tumor proliferation.(166,167) HDAC3 also regulates cancer progression through various pathways such as transforming growth factor β (TGFβ), Wnt, and interferon signaling.(167) Moreover, downregulation of HDAC3 helps to upregulate the vitamin D receptor (VDR) gene during cellular arrest in various cancer cells.(167−169) HDAC3 also indirectly modulates the acetylation of tubulin protein as seen in the PC3 cell line.(170) HDAC3 is associated with the transcriptional modulation of numerous cytokines implicated in immune responses related to cancer and inflammation.(171) The pro-IL-16 protein forms a complex with HDAC3, which results in the suppression of Skp2 gene transcription, which in turn leads to the cell cycle arrest.(172) HDAC3 also suppresses the activity of GATA binding protein 2 (GATA2), which has been correlated with non-small-cell lung cancer (NSCLC) governed by Ras protein.(173,174) HDAC3 was also found to deacetylate STAT1 to modulate its phosphorylation as well as nuclear translocation.(175) During mitosis, HDAC3 is complexed with A-kinase anchor protein 95 (AKAP95) and HA95 protein, which are required for histone deacetylation. Again, HDAC3 and AKAP95/HA95 are also important for phosphorylation of histone H3 at Ser10 (i.e., H3S10 phosphorylation). HDAC3 inhibition may therefore cause a decrease in H3S10 phosphorylation along with an increased level in histone acetylation in mitotic cell cycle arrest.(134) Nevertheless, the activity of HDAC3 is divergently mediated through phosphorylation of c-Jun N-terminal kinase (JNK) in triple-negative breast cancer (TNBC).(176) Apart from that, the JNK phosphorylation also increases HDAC3 phosphorylation affecting both inhibitor binding and enzymatic activity in breast cancer. In ERα-positive MCF-7 cells, HDAC3 knockdown (but not HDAC1 or HDAC2) decreases the level of estrogen receptor α (ERα) mRNA as well as the ERα protein.(177) Moreover, the knockdown of HDAC3 decreases the stability of ERα mRNA, estrogen-mediated cyclin D1 expression, and estrogen-dependent proliferation of ERα-positive MCF-7 cells (Figure 10).(177)
Figure 10
Figure 10. Role of HDAC3 in estrogen-dependent cyclin D1 expression.
Cui et al.(178) showed that HDAC3 expression is negatively associated with the expression of both estrogen receptor (ER) and progesterone receptor (PR) but positively linked with the overexpression of human epidermal growth factor 2 (HER2) along with the clinical condition of breast cancer. Therefore, HDAC3 is considered as a prognostic marker in invasive ductal breast cancer. Kim et al.(179) showed that HDAC3 selectively interacts with CREB3 (HDAC1, HDAC2, and HDAC8 having no interaction) to regulate transcription and migration in metastatic breast cancer. HDAC3 overexpression is found to repress CREB3-enhanced NF-κB activation of XIAP and NR4A2 genes. HDAC3 also selectively suppresses CREB3-mediated CXCR4 transcription in the MDAMB-231 cell line. Therefore, HDAC3 negatively regulates CREB3-modulated transcription and signaling pathways in metastatic breast cancer.
Hu et al.(180) showed that HDAC3 overexpression enhances the programmed death ligand-1 (PD-L1) mRNA levels in both MIA PaCa-2 and BxPC-3 cell lines. Inhibition of HDAC3 by RGFP966 (22) (structure and enzyme inhibition profile is provided in Figure 17) helps to reduce significantly the level of PD-L1 at the transcriptional level in both these cell lines in a dose-dependent fashion along with the disruption of the HDAC3/STAT3/PD-L1 pathway (Figure 11).
Figure 11
Figure 11. HDAC3 inhibition by RGFP966 (22) modulates the disruption of HDAC3/STAT3/PD-L1 pathway.
It has been reported that HDAC3 is overexpressed in glioma cells. The probable involvement of HDAC3 in the development of vasculogenic mimicry (VM)-positive glioma has been proposed by Liu et al.(181) HDAC3 activates PI3K and ERK1/ERK2, which further stimulate pro-MMP-14 and pro-MMP-2 resulting in the activation of MMP-14 and MMP-2, respectively. The activated MMP-2 and MMP-14 further cleave the laminin5γ2 (LAMC2) into promigratory fragments Ln5γ2′ and Ln5γ2x, which are involved in the formation of VM networks in glioma (Figure 12).
Figure 12
Figure 12. Role of HDAC3 to form VM networks in glioma. Adapted with permission from ref (181). Copyright 2015 John Wiley and Sons.
Zhang et al.(182) showed that selective inhibition of HDAC3 by RGFP966 (22) (5 μM and 10 μM) enhances TRAIL-mediated apoptotic cell death in colon cancer through modulating the death receptor 5 (DR5).
McLeod et al.(183) showed that selective inhibition of HDAC3 by RGFP966 (22) (40 mg/kg body weight three times a week for 3 weeks) triggers the inhibition of R1881-induced activation of androgen receptor (AR) genes such as PSA and NKX3-1 in LNCaP prostate cancer cells with an increase in acetylation of histone H3. Therefore, RGFP966 (22) may be useful in the treatment of castration-resistant prostate cancer (CRPC).(183) In hepatocellular carcinoma (HCC), HDAC3 knockdown increases the miR-195 level.(184,185) Moreover, selective inhibition of HDAC3 helps to activate miR-195 via transcription in HCC. Similarly, both HDAC3 mRNA and protein are found to be highly overexpressed in gastric carcinoma (GC).(184,186)HDAC3 knockdown significantly decreases the tumor weight as well as the colony-forming ability of GC cells. Again, HDAC3 inhibition helps in the downregulation of the miR-454 as well as upregulation of the chromodomain helicase DNA-binding protein 5 (CHD5), which could be a fruitful strategy to combat GC. Yin and co-workers(187) demonstrated the overexpression of HDAC3 in cholangiocarcinoma (CCA), and selective inhibition of HDAC3 by MI-192 (23) (structure and enzyme inhibition profile is provided in Figure 17) decreased cellular viability in CCA cell lines (IC50 = 6 μM at 48 h). Moreover, HDAC3 knockdown along with treatment with MI-192 (23) was found to induce the cleavage of poly-ADP ribose polymerase (PARP) as well as p53 expression to promote apoptosis in CCA. Interestingly, MI-192 (23) also inhibited the deacetylation by HDAC3 but not that by HDAC1 and HDAC2. It also effectively inhibited a CCA-xenografted tumor, suggesting it to be a potential therapeutic agent to combat CCA. Nevertheless, HDAC3 overexpression is the self-sufficient reason for poor prognosis in CCA patients.(188) Inhibition of HDAC3 by domatinostat/4SC-202 (17) (Figure 4, Table 3) and BG45 (24) (structure and enzyme inhibition profile is provided in Figure 17) helps decrease cellular viability and colony formation and induces apoptosis. Selective HDAC3 inhibition might be a valuable strategy to combat cutaneous T-cell lymphoma (CTCL). HDAC3-selective inhibitor RGFP966 (22) (at 10 μM for 24 h) increases the acetylation of H3K9/K14, H3K27, and H4K5 in CTCL cell lines HH and Hut78.(189) Due to HDAC3 inhibition by RGFP966, there is an increase in γH2aX, which indicates DNA damage and impeded S-phase cellular proliferation in CTCL. Again, Gupta et al.(190) found a higher level of HDAC3 expression in pSTAT3-positive diffused large B-cell lymphoma (DLBCL). Moreover, knockdown of HDAC3 upregulated the acetylation of STAT3Lys685 but hindered STAT3Tyr705 phosphorylation and inhibited the growth of pSTAT-positive DLBCL cells. According to Narita and co-workers,(191) HDAC3 inhibition by antisense RNA oligonucleotide-induced G2/M phase arrest triggers apoptosis in human maxillary carcinoma (HMC) IM-3 cell line through heating at acidic conditions. Nevertheless, the knockdown of HDAC3 (but not HDAC1 and HDAC2), along with downregulating serine and tyrosine phosphorylation of STAT3, triggers the cleavage of PARP and caspase-3 in multiple myeloma (MM).(136) Treatment with HDAC3-selective inhibitor BG45 (24) showed dose-dependent inhibition in MM cells (1.875 μM to 30 μM for 48 and 72 h) following caspase-3 and PARP-mediated apoptosis (Figure 13). Interestingly, it has also been proven that BG45 (24) does not display any effect on the acetylation of α-tubulin, suggesting its HDAC3 selectivity over HDAC6.
Figure 13
Figure 13. Inhibition of HDAC3 by BG45 (24) modulates the caspase-3 and PARP-mediated apoptotic pathway.
Bone marrow stromal cells (BMSCs) of patients having multiple myeloma are found to modulate a higher level of HDAC3 expression compared to BMSCs of healthy donors.(192) It is interesting to note that HDAC3-selective inhibitor BG45 (24) does not stimulate significant BMSC growth inhibition, but the knockdown of HDAC3 markedly inhibits endothelial tube formation. This suggests that HDAC3 has a critical role in bone marrow endothelial cells (BMECs) for neo-angiogenesis. The knockdown of HDAC3 in BMSC increases the secretion of soluble glycoprotein 130 (sgp130), and subsequently, the IL-1 trans-signaling pathway in multiple myeloma is hindered. HDAC3 knockdown triggers the downregulation of p-STAT3 and p-RB1 along with an increase in p21, without any change in AKT and ERK. Various analyses (such as MTT assay, Western blot, RT-PCR, and immunohistochemistry study) suggest the effective roles of HDAC3 in leukemia.(193) The knockdown or inhibition of HDAC3 decreases IkBα expression as well as expression of TNFα, IL-1β, and IL-18. Inhibition of HDAC3 by TSA (4) helps to trigger the apoptotic signaling pathways through the modulation of BAD, Cyto-C, and Bcl-xL proteins followed by the activation of caspase-3 and caspase-7 in leukemia. Long et al.(164) showed that combined treatment with valproic acid (VPA) (300 mg/kg), doxorubicin (3 mg/kg), and Ara-C (100 mg/kg) administered once daily for 5 days downregulated the expression of HDAC3 in K562/Doxo or THP-1 cells. Interestingly, AKT selectively tethers with HDAC3 but not with other HDACs. Moreover, the deacetylation of Lys20 is crucial for HDAC3-modulated activation of AKT.(194) The knockdown of HDAC3 or selective inhibition by RGFP966 (22) (3 μM for 24 h) enhances AKT acetylation, decreases AKT phosphorylation, and dissociates HDAC3 from AKT. Therefore, HDAC3 inhibition downregulates AKT and sensitizes leukemia cells to cytotoxicity upon treatment with anticancer agents. Moreover, depletion of HDAC3 along with treatment with RGFP966 (22) increases the survival time in acute myeloid leukemia (AML). As per the observation of Xu et al.,(195) SAHA (1) (5 μM for 48 h) downregulates HDAC3 expression, which is related to decreased expression of Bcr-Abl and c-Myc proteins in the BV-173 chronic myeloid leukemia (CML) cell line. Harada et al.(196) showed that HDAC3 knockdown along with HDAC3 inhibition with BG45 (24) (20 μM for 48 h) downregulates DNA methyltransferase 1 (DNMT1) in multiple myeloma. HDAC3 inhibitors stimulate the degradation of c-Myc, which upregulates the expression of DNMT1. Nevertheless, HDAC3 inhibitors by enhancing DNMT1 hyperacetylation decrease its stability. Moreover, the knockdown of HDAC3 significantly reduces the expression of XIAP and Bcl-2 proteins related to apoptosis. Combination therapy with BG45 (24) and DNMT1 inhibitor 5-azacytidine was found to synergistically downregulate DNMT1 to reduce tumor growth and induce apoptosis in multiple myeloma. Lombard et al.(197) further proposed that HDAC3 strongly reduces the level of ETS family transcription factors, ELK1 and ELK3. Again, HDAC inhibitors ameliorate the MAPK pathway inhibitors in BRAF, NRAS, PTEN, and NF1 mutant melanoma. Therefore, combination therapy with BRAF/MEK/HDAC3 inhibitors might be helpful to suppress the genes related to DNA repair, followed by the destruction of melanoma cells. Escaffit et al.(198) demonstrated that proteolytic cleavage of HDAC3 and cytoplasmic relocalization is crucial for apoptosis, whereas forced nuclear localization of HDAC3 reduces apoptotic efficacy. Moreover, the cleavage of HDAC3 increases histone acetylation along with the activation of transcription of pro-apoptotic genes during apoptosis.(199)
He et al.(200) reported that apart from HDAC3 overexpression in colorectal cancer, HDAC3 negatively correlates with A-kinase anchor protein 12 (AKAP12), which is a tumor suppressor in colorectal cancer. TSA (4) and RGFP966 (22) increase the expression of AKAP12 by inhibiting HDAC3. Ma et al.(201) showed that HDAC3 is a target related to the transcription of EWS-FL11. Entinostat (15, Figure 4, Table 3), a dual HDAC1/3-selective inhibitor, inhibited the growth of Ewing sarcoma (ES) cells. Entinostat (15, Figure 4, Table 3) not only arrests cells at G0/G1 phase but also enhances the expression of G1 gatekeeper p21Waf1/Cip1 followed by a decrease of cyclin D1 in ES. It also markedly enhances the ROS level as well as induces caspase-3/caspase-7 activity in TC-71 and CHLA-258 cell lines. Interestingly, the depletion of EWS-FL11 expression results in a marked reduction in cyclin D1 as well as HDAC3 but not in HDAC1. Therefore, it may be postulated that HDAC3 (but not HDAC1) is a downstream regulator of EWS-FL11 expression. Entinostat (15, Figure 4, Table 3) also hyperacetylates HSP90 followed by the depletion of EWS-FL11, BRCA1, BRCA2, and RAD51 proteins in ES cells. Therefore, it may be suggested that ES is dependent on EWS-FL11/HDAC3/HSP90 signaling and combination therapy with entinostat (15) along with inhibitors of HSP90 and PARP and DNA-damaging compounds may be a fruitful strategy to combat ES.(201) In this context, it may be inferred from the above-mentioned discussions that HDAC3 plays crucial roles in modulating a variety of cancers through diverse cellular mechanisms. Though several mechanisms of HDAC3 are still unknown, a number of lines of evidence suggest that selective inhibition of HDAC3 by specific HDAC3 inhibitors such as RGFP966 (22), MI-192 (23) and BG45 (24) may be effective to combat specific cancers. Therefore, HDAC3 is a potential emerging target for designing novel and selective HDAC3 inhibitors as drug candidates for the management of a variety of cancers.
3.2. HDAC3 in Diabetes
HDAC3 may be a key player in modulating diabetes as supported by a number of findings. Three single nucleotide polymorphisms (SNPs) of HDAC3 are found to be correlated with the risk of type-II diabetes in the Chinese population.(202) Moreover, during treatment with BRD3308 (25) (structure and enzyme inhibition profile is provided in Figure 19) in the ZDF rat model of type-II diabetes, there is a selective HDAC3 inhibition that helps to improve plasma glucose level along with a protective effect on pancreatic β-cells.(203) In addition, selective HDAC3 inhibition by BRD3308 (25) (10 μM for 24 h) reduces apoptosis in pancreatic β-cells through a reduction in caspase-3 activity.(204) During inflammatory conditions, HDAC3 expression is promoted by NF-κB, which in turn helps in the reduction of PPARγ activity.(205,206) HDAC3 is associated with inhibitor kappa Bα (IkBα) in cytosol. After the degradation of IkBα, HDAC3 enters the nucleus and inhibits the PPARγ activity through TNFα and subsequently modulates glucose and lipid metabolism.(206) Moreover, HDAC3 inhibition also induces the acetylation of PPARγ as well as stimulates the expression of PPARγ target genes (namely aP2 and adiponectin) and increases insulin sensitivity in type-II diabetes.(207) Apart from that, HDAC3 knockdown or HDAC3 inhibition enhances the stimulation of insulin signaling and glucose uptake. Interestingly, inhibition of HDAC3 was enough to enhance the transcription of PPARγ in the absence of thiazolidinediones. Therefore, a selective HDAC3 inhibitor may be highly effective in combating type-II diabetes by increasing insulin sensitivity without any adverse effects exerted by PPARγ ligands.(207) Further, HDAC3 knockdown was found to restore glucose stimulated insulin secretion (GSIS).(205,208) Meier and Wagner(155) proposed that HDAC1/3 inhibitors have a better effect in pancreatic β-cell apoptosis by distinct reduction of cellular nitrite along with GSIS. However, HDAC1 and HDAC2 inhibitors do not exhibit any protective effect. This suggests that HDAC3 inhibitors might be more beneficial in regulating the pancreatic β-cell apoptosis. Moreover, HDAC3 inhibitors may trigger fibroblast growth factor 21 (FGF21), a crucial modulator of lipid metabolism in the liver, to control the gluconeogenesis along with pancreatic β-cell protection by stimulating oxidative metabolism.(155)
Xu et al.(209) found that HDAC3 activity is markedly enhanced in hearts of diabetic mice and treatment with RGFP966 (22) (10 mg/kg sc every other day for 3 months) decreased cardiac HDAC3 activity. Moreover, RGFP966 (22) treatment helps to prevent diabetes-associated cardiac remodelling by reducing the accumulation of collagen and the expression of connective tissue growth factor (CTGF) and fibronectin-1 (FN-1) in diabetic cardiomyopathy (DCM). RGFP966 (22) treatment also reduces diabetic-induced oxidative stress along with the expression of plasminogen activator inhibitor-1 (PAI-1) and TNF-α in diabetic hearts. The treatment with RGFP966 (22) reversed diabetes-induced insulin resistance in heart as evidenced by the upregulation of insulin receptor substrate-1 (IRS-1) along with AKT phosphorylation, and GLUT4 expression. Nevertheless, treatment with RGFP966 (22) blocked the activation of cardiac ERK1/ERK2 but not that of JNK or p38 MAPK in OVE26 diabetic mice. Again, HDAC3 inhibition enhances the acetylation of histone H3 on the DUSP5 gene promoter region. Therefore, HDAC3 inhibition contributes significantly to the epigenetic modification of the DUSP5–ERK1/2 pathway as a therapeutic approach to combat DCM.(209) All these observations strongly support the crucial roles of selective HDAC3 inhibition as effective antidiabetic therapy. From the above discussions, it is clearly indicated that HDAC3 plays distinct roles in modulating diabetes and related disorders. Selective HDAC3 inhibition by compounds such as RGFP966 (22) and BRD3308 (25) is also effective in controlling diabetes and related cardiomyopathy. Therefore, highly selective HDAC3 inhibitors may be evaluated extensively to identify novel drug candidates as an armament against diabetes.
3.3. HDAC3 in Obesity
As far as obesity is concerned, inactivation of HDAC3 helps to upregulate several genes (such as Acab, Gpam, Elvol3, and Fasn) along with downregulation of several genes (namely, Acads, Acls5, Cpt1b, and Crot) related to lipidogenesis, fatty liver, and lipid oxidation in myocardium.(210−213) Additionally, HDAC3 deletion induces the expression of genes associated with lipid metabolism (such as Scd1 and Scd2), which may be due to the dysregulation of PPAR nuclear receptors.(210) HDAC3 was also found to repress fatty acid oxidation genes by modulating PPAR in intestinal epithelium. HDAC3-selective inhibitor RGFP966 (22) (150 mg/kg po for 8 days) activated the expression of fatty acid oxidation genes, that is, mitochondrial β-oxidation genes and peroxisomal β-oxidation genes in small intestine, as evaluated in C57B2/6 WT mice.(210)HDAC3 deletion in heart also produced severe hypertrophic cardiomyopathy with reduced survival rates in the presence of high fat diet,(213) but complete knock out of HDAC3 was found to be embryonic lethal.(214) HDAC3 also reduced the transcription of phosphoenolpyruvate carboxykinase (PEPCK) by inhibiting PPARγ and CREB. This mechanism clearly highlights crucial roles of HDAC3 in glycerogenesis in adipose tissue and lipodystrophy as tested in aP2-p65 transgenic mice.(215) In the liver, HDAC3 also regulates circadian-mediated lipid metabolism.(205) HDAC3 inactivation in heart and muscle decreases fatty acid catabolism in diet-induced obese (DIO) mice.(213) Not only that, inhibition of HDAC3 helps to restore PPARγ function in obesity. TSA (4) is found to block HDAC3 activity effectively in DIO mice.(205) Though there are not many experimental data, it is clear from the above discussion that HDAC3 has a direct correlation with lipid metabolism through genetic manipulations and hyperactivity of HDAC3 induces obesity. Moreover, selective HDAC3 inhibition by RGFP966 (22) also activates fatty acid oxidation genes, and therefore, HDAC3 can be considered as a novel biomolecular target, and selective HDAC3 inhibition with highly potent inhibitors might be a potential therapeutic strategy to open up a new vista in treating obesity.
3.4. HDAC3 in Neurodegenerative Disorders
A number of studies reveal critical roles of HDAC3 in neurodegenerative disorders. Schmitt et al.(216) demonstrated that HDAC3 plays a crucial role in the death of retinal ganglion cells (RGCs) after acute optic nerve injury. Deletion of HDAC3 in RGCs results in optical nerve crush (ONC)-induced nuclear atrophic characteristics, namely, formation of heterochromatin along with the loss of nuclear structure.(216) Selective HDAC3 inhibition with RGFP966 (22) (2 μM) is found to prevent the above-mentioned nuclear atrophies after ONC.(217) Repeated intraperitoneal administration of RGFP966 (22) reduced the loss of RGCs after ONC without exerting any off-target toxic effects. Therefore, selective inhibition of HDAC3 may be targeted for the treatment of ONC. Norwood and co-workers(218) explained that HDAC3 is crucial for the proper development of the brain. Moreover, depletion of HDAC3 from CNS progenitor cells leads to severe abnormalities in the neocortex and cerebellum and subsequent perinatal death of mice. HDAC3 regulates the activity of glial fibrillary acidic protein (GFAP) at the transcription level. Further, conditional knockout of HDAC3 from neurons of the forebrain resulted in neurological disorders, namely, forepaw clasping, ataxia, and paralysis followed by death. HDAC3 is an important factor related to huntingtin-induced neurodegeneration.(147) HDAC3, liberated from mutant huntingtin, was found to take part in modulating the neurotoxic activity. Knockdown of HDAC3 was found to inhibit mutant huntingtin neurotoxicity, and neurotoxicity is significantly decreased in HDAC3-deficient neurons. HDAC3 inhibitors were found to be effective against Friedreich’s ataxia.(219,220) Xia et al.(221) demonstrated that RGFP966 (22) (15 μM for 1 h) by selective inhibition of HDAC3 reduced LPS-induced proteins in microglia in neurological disorders. Selective HDAC3 inhibition by RGFP966 (22) is supposed to downregulate the STAT3/STAT5 pathway, the Toll-like receptor signaling pathway (namely, TLR2, TLR3, and TLR6), and MAPK p38 and spleen tyrosine kinase (SYK). Selective HDAC3 inhibition by RGFP966 (22) also decreased inflammatory responses in CNS.(184,221) RGFP966 (22) through HDAC3 inhibition decreased TNF-α and IL-6 as well as blocking the activation of STAT3 and STAT5. Therefore, HDAC3 might be a valuable target to combat microglial activation and inflammation of neurodegenerative disease. Jia et al.(222) demonstrated that by selective inhibition of HDAC3, RGFP966 (22) (10 and 25 mg/kg, 3 injections/week sc for 10 weeks) improved the motor deficits and provided neuroprotective effects on striatal volume. However, it did not markedly alter the chemokine and cytokine genetic expression levels but did alter the striatal expression of macrophage migration inhibitory factor (MIF) related to the activation of glial cells in N171-82Q transgenic mice. Moreover, RGFP966 (22) also caused a reduction in glial fibrillary acidic protein (GFAP) immunoreactivity in the striatum of N171-82Q transgenic mice. These observations suggest that inhibition of HDAC3 might be effective in treating Huntington’s disease (HD). Suelves et al.(223) further suggested that HDAC3 has crucial roles in the impairment of long-term memory in HD. RGFP966 (22) by selective inhibition of HDAC3 reduced the activity of HDAC3 in hippocampus and striatum when administered through subcutaneous route in HdhQ7/Q7 wild-type (WT) and HdhQ7/Q111 knock-in (KI) mice. RGFP966 (22) (50 mg/kg sc three times/week for 3 to 6.5 months) was found to prevent or delay the impairment in recognition as well as spatial long-term memory in HD mice. Further, RGFP966 (22) by selective inhibition of HDAC3 in HD mice affects the expression of memory-related genes (such as Arc, Egr1, and c-Fos) essential for maintaining long-term memory and synaptic plasticity. Moreover, treatment with RGFP966 (22) was found to prevent deficits in corticostriatal-dependent motor learning skills. It also stabilized or repressed striatal CAG repeat expansions in HD mice. Not only that, RGFP966 (22) decreased the oligomerization of mutant huntingtin (mHtt) protein in striatum that is a distinctive feature of HD. HDAC3 was found to increase hippocampal-based object regulation and location memory along with drug-related memories.(224−226) By selective HDAC3 inhibition, RGFP966 (22) (30 mg/kg ip) helped to trigger memory in APP/PS1 mice.(224) McQuown and co-workers(227) showed that HDAC3 has pivotal roles in modulating enhanced memory in hippocampal-dependent object recognition. They also showed that the deletion of HDAC3 in the hippocampus might be effective in increasing novel object recognition (NOR). HDAC3-selective inhibitor RGFP966 (22) (10 mg/kg sc) increased hippocampal-dependent object memory.(226) It has also been observed that HDAC3 has an impact in cognitive diseases related to schizophrenia.(139) HDAC3-mediated epigenetic modulation has been found to regulate the inflammatory gene network in microglia after spinal cord injury (SCI).(140) HDAC3 inhibitor RGFP966 (22) suppressed inflammatory responses leading to neuronal protection and enhanced functional recovery in SCI. Moreover, HDAC3 inhibition helps to suppress IFNγ and TNFα, as well as a broad spectrum of inflammatory cytokines, leading to tissue repair in SCI. Additionally, Sanchez et al.(228) showed that selective HDAC3 inhibitor RGFP966 (22) (10 μM for 24 h) enhanced the expression of Arg-1, a well-known anti-inflammatory phenotype (M2) marker, and decreased the formation of foamy macrophages in SCI in vitro. However, the in vivo study revealed that HDAC3 inhibition by RGFP966 (22) (10 mg/kg ip for 3 days) did not exhibit any effect on the functional recovery of macrophage phenotype after SCI. Chen et al.(141) showed that valproic acid (VPA) (300 mg/kg/day ip for 3 days) decreased HDAC3 protein expression without affecting HDAC1 and HDAC2 in an injured or lesioned spinal cord. VPA decreased the HDAC3 activity in the nucleus but not in the cytosol. Therefore, it can be inferred that VPA shows neuroprotective efficacy and decreases HDAC3-mediated inflammatory responses in neurons and microglia in the case of SCI. VPA was found to increase STAT1 and NF-κB p65 acetylation. It also induced marked interactions between NF-κB p65 and STAT1. Subsequently, it inhibited nuclear translocations and DNA-binding ability after SCI. Yang et al.(229) showed that the nuclear localization of HDAC3 markedly decreased in brain ischemic preconditioning (PC) in vivo. By selective blocking of HDAC3, RGFP966 (22) imitated the neuroprotective effects related to PC in vivo after middle cerebral artery occlusion (MCAO). Moreover, knockdown of HDAC3 and inhibition of HDAC3 enhanced the acetylation of histones related to genes Bcl2l1, Hspa1a, and Prdx2, which may be associated with protection in the PC. Therefore, it may be inferred that HDAC3 inhibition helps in the PC of the brain and may be effective in protection against stroke. Spinocerebellar ataxia type-1 (SCA1) is caused by the misregulation of the ataxin-1 (ATXN1) gene, and HDAC3 inhibition may help to modulate ataxin-1 regulation.(122) Selective HDAC3 inhibition might be useful for preventing spinocerebellar ataxia type-7.(122,230) Krishna et al.(231) reported that RGFP966 (22) through the inhibition of HDAC3 hindered the impairment of amyloid-β oligomer-induced synaptic plasticity in CA1 pyramidal neurons, which can be effective in targeting Alzheimer’s disease. Therefore, from the above discussions, it might be inferred that HDAC3 plays crucial roles not only in the development of the brain but also in several neurodegenerative disorders (Huntington’s disease, Friedreich’s ataxia, etc.). Selective HDAC3 inhibition by RGFP966 (22) was also found to be effective in object recognition and memory enhancement. Therefore, it is well validated that potent HDAC3-selective inhibitors should be considered for the management of several neurodegenerative diseases.
3.5. HDAC3 in Rheumatoid Arthritis
HDAC3 plays crucial roles in modulating rheumatoid arthritis (RA). HDAC3 inhibitors reduce the IL-1β-induced expression of a number of modulators of RA, such as MMPs (namely, MMP-1 and MMP-3), interferon-β1 (IFNβ1), chemokines (namely, CCL2-3, CXCL9-11), and interleukins (namely IL-6 and IL-8)(138) (Figure 14). Furthermore, HDAC3 is also established as an epigenetic modulator of inflammation.(232,233)
Figure 14
Figure 14. Role of HDAC3 in arthritis.
HDAC3 also modulates STAT1 phosphorylation required for transcriptional activation. HDAC3 inhibitors inhibit the induction of STAT1 DNA-binding in RA fibroblast like synoviocytes (FLS) in response to IL-1β.(138) The selective inhibition of HDAC3 by MI-192 (23) (10 μM) inhibits the production of TNF along with IL-6 in PBMCs of RA patients.(232) HDAC3 has also a direct relation to osteoarthritis (OA).(234) HDAC3 expression in both nucleus and cytoplasm was markedly reduced in osteoarthritis + moderate intensity treadmill exercise group (OAM) compared to the osteoarthritis group (OAG). Apart from a greater level of ADAMTS5 and NF-κB mRNA, there was also a higher level of HDAC3 mRNA in OAM than in OAG. By inhibiting HDAC3, RGFP966 (22) (50 μM, intraarticular, 3 times/week for 4 weeks) decreased the level of IL-1β stimulation and subsequently NF-κB expression to exert a protective role in OA. Also, RGFP966 (22) by inhibiting HDAC3 selectively inhibited the nuclear translocation of NF-κB. RGFP966 (22) also inhibited ROS production in chondrocytes through inhibition of HDAC3. From the above discussion, it is obvious that HDAC3 plays crucial roles in the modulation of inflammatory mechanisms related to rheumatoid arthritis and osteoarthritis. Selective HDAC3 inhibition by MI-192 (23) and RGFP966 (22) has also been found to be effective in alleviating the symptoms of arthritis. Hence, it might be worth targeting HDAC3 with more potent inhibitors to delineate an effective treatment strategy for arthritis.
3.6. HDAC3 in Cardiovascular Disease and Hypertension
Hoeksema et al.(235) demonstrated that HDAC3 is the only HDAC enzyme having crucial roles in regulating atherosclerotic lesions. They found that deficiency of myeloid HDAC3 triggers deposition of collagen in atherosclerosis and stabilizes plaque phenotype. Moreover, depletion of HDAC3 triggers a soluble macrophage-secreted factor and helps in the production of collagen by vascular smooth muscle cells (VSMCs). In addition, deletion of HDAC3 triggers the upregulation of TGFβ, which stabilizes atherosclerotic lesions. Therefore, HDAC3 may be targeted to improve atherosclerotic conditions in cardiovascular diseases. Lewandowski et al.(236) demonstrated that HDAC3 modulates the epigenetic silencing of TGF-β1 in congenital heart disease. HDAC3 was also found to play crucial roles in hypertension. HDAC3 deacetylates the mineralocorticoid receptor (MR).(151) HDAC3 is the only enzyme among the class I HDACs that modulates the transcriptional activity of MR. Therefore, knockdown of HDAC3 or inhibition of HDAC3 results in reduced transcriptional activity of MR to prevent hypertension.(151)
Along with HDAC1 and HDAC2 levels, HDAC3 level was also found to be increased in a hypoxia-induced pulmonary hypertensive rat model.(237) Moreover, HDAC3 expression was found to be induced in spontaneously hypertensive rats (SHRs).(238) Nozik-Grayck and co-workers(152) showed that histone deacetylation through HDAC3 reduced the expression of extracellular superoxide dismutase (SOD) in pulmonary artery smooth muscle cells (PASMCs), and HDAC3 inhibitors help to protect against idiopathic pulmonary arterial hypertension (IPAH) by enhancing the level of PASMC SOD3 expression. HDAC3 was also found to be overexpressed in an experimental model of heart failure. The reduction of HDAC3 increases cardiac activity and lowers vascular fibrosis.(239,240) Ryu et al.(241) showed that selective HDAC3 inhibitor RGFP966 (22) (3 (mg/kg)/day for 7 days) markedly reduced systolic blood pressure, cardiac hypertrophy, and the thickness of the aortic wall in angiotensin-II-induced hypertensive mice. However, it did not show any effect in modulating eNOS uncoupling and oxidative stress in such mice.
Zhao et al.(242) showed that selective HDAC3 inhibition reduced the infarct volume in mice pretreated with RGFP966 (22) (10 mg/kg) and subjected to ischemia–reperfusion (I/R) injury (DIR-H) compared to untreated mice subjected to I/R injury (DIR). RGFP966 (22) treatment significantly increased SOD activity but reduced the level of malondialdehyde (MDA) and ROS in the DIR-H group compared to the DIR group of mice. HDAC3 inhibition by RGFP966 (22) exerted protective effects on cerebral I/R injury in diabetic mice. Apart from that, HDAC3 inhibition also increased autophagy in diabetic mice with cerebral I/R injury. HDAC3 inhibitor RGFP966 (22) was found to inhibit the diabetes-induced aorta damage by reducing hepatic Kelch-like ECH-associated protein-1 (Keap1) as well as by increasing the nuclear transcription of erythroid 2-related factor (Nrf2) and, subsequently, by increasing the activation of anti-inflammatory genes. HDAC3 inhibition also enhanced the expression of FGF21, which has a protective role in diabetes-induced aorta damage.(184,243) Also, the overexpression of HDAC3 was found to modulate the biosynthesis of cholesterol through repression of lanosterol synthase.(244) In this context, it is evident that HDAC3 is one of the crucial HDAC isoforms, playing pivotal roles in modulating cardiovascular disease and hypertension. Also, selective HDAC3 inhibitors such as RGFP966 (22) help to alleviate hypertensive states and atherosclerotic conditions. Therefore, selective HDAC3 inhibitors can be explored more extensively to identify effective drug candidates for the treatment of cardiovascular and hypertensive disorders.
3.7. Role of HDAC3 in Lung and Kidney Diseases
HDAC3 plays a pivotal role in lipopolysaccharide (LPS)-induced endothelial barrier dysfunction (EBD), which is a key factor in acute lung injury (ALI).(245) HDAC3 activity is enhanced during Ser24 phosphorylation that helps to translocate HDAC3 into the cytosol, where HDAC induces the deacetylation of heat shock protein 90 (HSP90) triggering chaperone activity following the Rho-ROCK pathway.(246) Steroid receptor coactivator (Src) localizes HDAC3 and further activates HSP90 followed by RhoA activity and the subsequent phosphorylation of ROCK protein, which in turn phosphorylates myosin light chain (MLC) to induce EBD. HDAC3-selective inhibitor RGFP966 (22) has been found to exert a protective effect on LPS-mediated ALI and EBD through regulating HSP90. Gu et al.(247) demonstrated that the deficiency of HDAC3 resulted in NF-κB-mediated transcriptional activation along with the overexpression of cytokines and, in turn, enhanced TGF-β/Smad responsible for the development of ALI. HDAC3 also deacetylated endothelial nitric oxide synthase (eNOS) in the cytoplasm and, subsequently, decreased vascular function.(248) HDAC3 helped to deacetylate p65 and subsequently negatively modulated TNF-α-induced luciferase activity, which is inhibited by TSA (4).(137) HDAC3 was also found to regulate IL-1 induced IL-8 or CXCL2 gene expression, as well as the inflammatory signaling, by deacetylating lysine residues 122, 123, 314, and 315 in NF-κB p65.(249) TSA (4) through the inhibition of HDAC3 led to a decrease of monocyte chemoattractant protein-1 (MCP-1) secretion. RGFP966 (22) by selective inhibition of HDAC3 decreased TNF-α-induced chemokine ligand 2 (CCL2).(137,250) By inhibiting HDAC3, RGFP966 (22) reduced cytokine IL-1β, IL-6, and IL-12b activity in macrophages and enhanced expression of anti-inflammatory gene IL-10 in precision-cut lung slices (PCLS) by modulating the transcriptional activity of NF-κB p65.(137,251) Lin et al.(252) showed that selective HDAC3 inhibition increased the acetylation of PPARγ and prevented the loss of Klotho (an antiaging protein expressed in kidney) and helped to retard the development of chronic kidney disease (CKD). As HDAC3 is a modulator of NF-κB-mediated inflammation, HDAC3 inhibitors may be efficacious for the management of chronic obstructive pulmonary disease (COPD) and asthma.(253) Apart from selective HDAC3 inhibition, promoting NF-κB transcriptional activity and siRNA-mediated HDAC3 downregulation also decreased the expression of pro-inflammatory genes (such as IL-1β, IL-6, etc.), which might have beneficial roles in COPD and asthma.(253) Moreover, along with HDAC1 and HDAC2, HDAC3 inhibition decreases pro-inflammatory cytokines in COPD. Entinostat (15) and TSA (4) have been found to effect reduced inflammatory responses in asthma and COPD via HDAC3 inhibition as evidenced by in vivo mouse models.(253) In light of the above-mentioned discussions, it is clearly indicated that HDAC3 has a correlation in the mechanisms associated with lung and kidney diseases, and selective inhibition of HDAC3 may be taken into consideration for the management of lung and kidney disorders.
3.8. HDAC3 in Protozoal and Viral Diseases
HDAC3 has been found to be a key regulator controlling genetic expression and cellular differentiation in apicomplexa Toxoplasma gondii.(254) Selective inhibition of T. gondii HDAC3 (TgHDAC3) by FR235222 increases the level of histone H4 acetylation and might be useful against acute and chronic toxoplasmosis. Regarding the hepatitis C virus (HCV), HDAC3 inhibitor RGFP966 (22) (10 μmol/L for 72 h) reduced the expression of mRNA in HCV replication.(255) Treatment with RGFP966 (10 μmol/L for 72 h) increased the level of liver-expressed antimicrobial peptide-1 (LEAP-1), whereas the level of apolipoprotein-A1 (Apo-A1), which is related to the life cycle of HCV, was decreased. Interestingly, RGFP966 (22) increased histone H3 acetylation around Apo-A1 transcriptional start sites (TSS) though Apo-A1 expression was decreased. Moreover, RGFP966 (22) prevented CCAAT-enhancer-binding protein α (C/EBPα) binding to the LEAP-1 promoter and increased HIF1α and STAT3 in HCV. Therefore, it may be inferred that HDAC3 inhibitors may be promising therapeutic agents against HCV. HDAC3 was also found to repress the transcription of human T-cell lymphocytic virus type-1 (HTLV-1).(256) Additionally, HDAC3 inhibition was found to be crucial for latent HIV-1 reactivation.(159) Interestingly, knockdown of HDAC3 (but not HDAC1 and HDAC2) produced significant cell death along with the reactivation of latent HIV-1 expression. Barton et al.(257) showed that inhibition of HDAC3 by BRD3308 (25) (concentration of 10 μM and greater after 12 h) induced the transcription of HIV-1 as evidenced in the 2D10 cell line. Moreover, treatment with 15 μM BRD3308 (25) overnight also induced the growth of HIV-1 from resting CD4+ T-cells of antiretroviral-treated and aviremic HIV-positive patients. These results suggested that inhibition of HDAC3 may be effective to combat HIV-1 infection. Moreover, HDAC3-selective inhibitors such as RGFP966 (22) and BRD3308 (25) were found to take part in modulating protozoal and viral diseases. Therefore, potent and selective HDAC3 inhibitors might be evaluated to identify novel therapy for the management of these protozoal and viral diseases.
3.9. The Role of HDAC3 in Other Diseases
HDAC3 has recently been found to play a crucial role in regulating the glycerol transporter aquaporin-3 (AQP-3) with p53 transcription factor involved.(258) HDAC3-selective inhibitors are effective in treating skin diseases such as psoriasis where AQP-3 is overexpressed.(258) Kim et al.(259) demonstrated that HDAC3 mediates allergic skin inflammation, namely, the triphasic cutaneous reaction (TpCR) and passive cutaneous anaphylaxis (PCA). HDAC3 has been shown to interact with FcεRIβ protein and with Src family protein Lyn upon antigenic response. This triggers the interaction between HDAC3 and Rac1, which is further responsible for the induction of c-Jun and Sp1. Both c-Jun and Sp1 bind to the MCP1 promoter region to promote the expression of MCP1 and, finally, modulate the allergic skin inflammation process. In another study, Kim et al.(260) demonstrated that DNMT1 is a negative regulator of HDAC3. Downregulation of DNMT1 induced HDAC3 expression and enhanced the expression of adhesion molecules, namely VCAM-1, ICAM-1, and integrin α5, to affect vascular permeability leading to allergic skin inflammation. Indirectly, HDAC3 along with SNAIL was induced by the interaction of transglutaminase II (TGase II) and NF-κB. HDAC3 further demonstrated transcriptional effect on E-cadherin, critically involved in allergic inflammation.(261) It was also found that TSA (4) decreases the recruitment of HDAC3 to the interferon regulatory factor (IRF5) promoter and suppresses IRF5 transcription.(262) HDAC3 is an activator during transcriptional regulation of IRF, which is a crucial factor in systemic lupus erythromatous (SLE). Moreover, IRF5 is also involved in immunological disorders, namely, inflammatory bowel disease, RA, and Sjogren’s syndrome. In addition, HDAC3 expression has been observed to be profound in penile fibrosis as well as in erectile dysfunction related to the bilateral cavernous nerve injury (BCNI). VPA decreases penile HDAC3 expression by lowering TGF-β1 and fibronectin expression in the penis.(263) Thus, inhibition of HDAC3 could be a treatment strategy for these penile disorders. It can be inferred that apart from playing important roles in major disease conditions (such as cancer, diabetes, neurodegenerative, and cardiovascular disorders), HDAC3 has crucial roles in modulating neglected diseases (such as skin diseases, allergy, penile erection, etc.). As there are not many reports, the roles of HDAC3 need to be explored more critically, and inhibition of HDAC3 might emerge as a treatment option for the above-mentioned neglected diseases.
4. HDAC3-Selective Inhibitors
ARTICLE SECTIONS
Considering the importance and the crucial role of HDAC3 in diverse disease conditions, selective HDAC3 inhibition can be considered as a promising therapeutic strategy to combat disease conditions without exerting severe off-target effects. In that context, various potent and selective HDAC3 inhibitors have been discussed in the following sections to understand their importance in various disease conditions.
4.1. Hydroxamates as HDAC3-Selective Inhibitors
Tapadar et al.(264) reported some HDAC inhibitors containing an isoxazole group in the linker region adjacent to the hydroxamate group. The cap region of such compounds was modified with various aryl, heteroaryl, and alicyclic functions. It was interesting to note that the thiazolylphenyl moiety as a cap group (26, Figure 15) resulted in potent and selective HDAC3 inhibition (IC50 = 30 nM) maintaining a minimum of 2-fold selectivity over the other HDACs.
Figure 15
Figure 15. Hydroxamates as potent and HDAC3-selective inhibitors.
Compound 26 was found to be highly cytotoxic against a variety of pancreatic cancer cell lines, namely, Mia Paca-2 (IC50 = 4 μM), HupT3 (IC50 = 1 μM), Panc 04.03 (IC50 = 4 μM), Su.86.86 (IC50 = 1 μM), and BxPC-3 (IC50 = 3 μM).
Neelarapu and co-workers(265) reported some hydroxamates based on arylisoxazole and arylpyrazole moieties as dual inhibitors of HDAC3 and HDAC8. It is interesting to note that the isoxazole compounds exhibited higher HDAC3 selectivity over HDAC8, but the pyrazoles were nonselective inhibitors. Compound 27 (Figure 15) exerted potent and selective HDAC3 inhibition over HDAC8. Compound 27 induced the accumulation of acetylated histone H4 in the differentiated SH-SY5Y neuroblastoma cell line at lower concentration. Compound 27 did not exhibit any cytotoxicity but showed neuroprotective effects from chemical-induced apoptosis in retinoic acid differentiated cell line SH-SY5Y.
Thaler et al.(266) reported some spiro[2H-(1,3)-benzoxazine-2–4′-piperidine]-based hydroxamates as potential HDAC inhibitors. Compound 28 exhibited selective HDAC3 inhibitory activity (IC50 = 65 nM) over the other HDACs (Figure 15). It was also effective in exerting cytotoxicity in cancer cell lines K562 (IC50 = 399 nM), A549 (IC50 = 773 nM), and HCT-116 (IC50 = 477 nM), along with a good pharmacokinetic profile and oral bioavailability.
Thaler et al.(267) further reported a series of spiro[chromane-2,4′-piperidine] derivatives as potential HDAC inhibitors as well as cytotoxic agents against K562, A549, and HCT116 in sub-micromolar concentration. Compound 29 (Figure 15) exhibited potent and selective HDAC3 inhibition (IC50 = 90 nM) over other HDACs. It also displayed potential cytotoxicity against cancer cell lines K562 (IC50 = 0.681 μM), A549 (IC50 = 1.322 μM), and HCT-116 (IC50 = 0.777 μM). Again, compound 29 enhanced histone acetylation in K562 cells in a dose-dependent manner as confirmed by flow cytometry analysis. Compound 29 also enhanced the G0/G1 phase population, followed by a reduction in S and G2/M phase populations with a lower dose, but it increased with a higher dose. In the xenograft model induced with HCT-116 colon cancer, compound 29 was also found to show effective antiproliferative efficacy. Modification at the spiro function along with various substitutions at the piperidine moiety by the same group of researchers yielded another series of compounds.(268) Compounds 30 and 31 (Figure 15) demonstrated potent and selective HDAC3 inhibition (IC50 = 28 nM and 30 nM, respectively) maintaining a minimum of 2-fold selectivity over the other HDACs. Both of them showed potent cytotoxicity in cancer cell lines K562, A549, and HCT116.
Choi et al.(269) reported a triazine analog containing a pyrazole group attached to the hydroxamate moiety through a tetramethylene function (32, Figure 15). It exhibited potent and selective HDAC3-inhibitory activity (IC50 = 7 nM) over the other HDACs. It also showed potent cytotoxic efficacy in a variety of lymphoma cell lines, namely, TMD-8 (GI50 = 3 nM), HBL-1 (GI50 = 30 nM), U2932 (GI50 = 148 nM), RC-K8 (GI50 = 94 nM), and SU-DHL-4 (GI50 = 62 nM), along with good drug metabolism and pharmacokinetics (DMPK) profile. An N-hydroxycinnamamide derivative (33, Figure 15) containing an indole cap group, reported by Zang et al.,(270) resulted in potent HDAC3 inhibitory activity (IC50 = 7.5 nM) that was highly selective over HDAC1, -2, and -6.
Cheng et al.(271) designed and synthesized some indole-based hydroxamates as dual HDAC/BRD4 inhibitors. Compound 34 (Figure 16) was a potent HDAC3 inhibitor (IC50 = 23 nM) maintaining a minimum of 5-fold selectivity over HDAC1 (IC50 = 179 nM) and HDAC2 (IC50 = 118 nM).
Figure 16
Figure 16. Indole-based hydroxamates as potent and HDAC3-selective inhibitors.
A p-fluoro substitution at the benzyl group of compound 34 produced compound 35 (Figure 16). It was 4-fold more potent for HDAC3 (IC50 = 5 nM) compared to compound 34. It was also more than 36-fold HDAC3-selective over HDAC1 (IC50 = 181 nM) and HDAC2 (IC50 = 298 nM). Reduction of a methylene spacer between the indole moiety and hydroxamate function of compound 35 led to the development of compound 36 (Figure 16). Compound 36 was also a potent HDAC3 inhibitor (IC50 = 39 nM) selective over HDAC1 (IC50 = 341 nM) and HDAC2 (IC50 = 517 nM). When the benzyl moiety of compound 34 was replaced with a phenylethyl moiety, compound 37 (Figure 16) was produced. It showed similar HDAC3 inhibitory potency as well as selectivity (HDAC3 IC50 = 28 nM; HDAC1 IC50 = 240 nM; HDAC2 IC50 = 139 nM). A five-methylene spacer group between the indole and hydroxamate moiety, instead of the six-methylene spacer of compound 37, led to the development of compound 38 (Figure 16). Compound 38 was about 3-fold less potent for HDAC3 inhibition (IC50 = 76 nM) than compound 37 though it was also selective over HDAC1 (IC50 = 247 nM) and HDAC2 (IC50 = 538 nM). The p-fluoro substitution at the phenylethyl moiety of compound 38 led to the discovery of compound 39 (Figure 16), which was also a potent and HDAC3-selective inhibitor (IC50 = 17 nM) compared with HDAC1 (IC50 = 259 nM) and HDAC2 (IC50 = 946 nM). Methyl substitution was also tried at the benzyl moiety at ortho, meta, and para positions for compound 34 keeping the six-methylene spacer between the indole and hydroxamate moieties unaltered. That led to the development of compounds 40–42 (Figure 16). They were also highly potent HDAC3-selective inhibitors. In the case of the five-methylene spacer between the indole and hydroxamate function, the ortho-methyl, meta-methyl, and para-methyl substitution led to the development of compounds 43–45 (Figure 16). They were also potent HDAC3-selective inhibitors. However, compounds with the six-methylene spacer were better HDAC3 inhibitors than the corresponding five-methylene spacer analogs (40 > 43; 41 > 44; 42 > 45). These compounds were found to be cytotoxic against human acute leukemia THP-1 cell line. The best active HDAC3 inhibitor, compound 35, also showed effective cytotoxicity (GI50 = 15.5 μM) though it was less cytotoxic than other compounds in this series (compounds 34, 37–39, 44–45). Compound 35 was found to acetylate histone H3 but not α-tubulin in THP-1 cell. This proved that compound 35 is a HDAC3-selective inhibitor. Compound 35 effectively reduced the c-Myc level in a dose-dependent fashion. The molecular docking analysis between HDAC3 and compound 35 revealed that the hydroxamate moiety coordinates the Zn2+ ion. Two hydrogen bonds were noticed between the amide group of hydroxamate moiety and His134 and His135. The indole moiety took part in hydrophobic and van der Waals interactions with amino acid residues Phe199 and Phe200, respectively. Moreover, the phenyl group was also found to form hydrophobic interaction with Leu266. The fluorine atom also interacted with Arg266.
4.2. Benzamide-Based HDAC3-Selective Inhibitors
A series of benzamide-derived HDAC3 inhibitors selective over the other HDAC isoforms (HDAC1, HDAC2, HDAC6, HDAC8, and HDAC10) were reported by Chen and co-workers.(272) These compounds were found to be potent and highly selective compared to MS-275. The SAR analysis revealed that the six-methylene linker based benzamide derivative containing triazolophenyl substitution at the meta position of the phenyl group (46, Figure 17) demonstrated highly potent HDAC3 inhibition (IC50 = 120 nM) compared to MS-275 (IC50 = 2311 nM). It was also very highly HDAC3-selective (∼250-fold) over other isoforms of HDAC.
Figure 17
Figure 17. Some benzamide-based HDAC3-selective inhibitors.
Modification of the phenyl ring with a thiazole ring, as well as elimination of the triazole moiety, of compound 46 led to some effective and HDAC3-selective inhibitors (47–49, Figure 17). It was interesting to note that the thiazole compounds (47, 49) showed better HDAC3 inhibitory potency than the corresponding phenyl derivative (46) but they were lesser HDAC3-selective. Surprisingly, these compounds were unable to exert any neuroprotective effects.(251) Compound 46 was also evaluated against a panel of pancreatic cancer cell lines (such as BxPC-3, HupT3, Mia Paca-2, Panc04.03, and SU 86.86).(273) It was inactive in almost all the cell lines except in SU 86.86, where it was moderately active (IC50 = 32 μM).
Malvaez and co-workers(226) synthesized a unique benzamide molecule called RGFP966 (22, Figure 17). There is a p-fluoro group attached to the benzamide scaffold. A pyrazole moiety is attached to the benzamide moiety through an unsaturated alkylcarbonyl function. Additionally, the pyrazole group is attached to the terminal phenyl group through another unsaturated alkyl group. It is a highly potent HDAC3 inhibitor (IC50 = 80 nM) with a high degree of selectivity over all other HDACs (IC50 > 15000 nM). Various in vitro and in vivo studies have been conducted with RGFP966 (22) as a reference molecule due to higher HDAC3 inhibitory potency and high degree of selectivity. Boissinot et al.(274) synthesized a potent HDAC3 inhibitor, MI-192 (23, Figure 17), with an IC50 of 16 nM and selectivity over several other HDACs (HDAC1, -4, -6, -7, and -8) but not over HDAC2 (IC50 = 30 nM). MI-192 (23, Figure 17) was screened against a panel of cancer cell lines, namely, non-small-cell lung, ovarian, colon, CNS, breast, prostate, renal, melanoma, and leukemia lines. In all these cancer cell lines, MI-192 (23) was found to be cytotoxic at low micromolar concentration. Interestingly, it exhibited better efficacy than MS-275 (15) only in leukemia cell lines; however, it showed lower efficacy in the rest of the cell lines compared to MS-275 (15). Nevertheless, MI-192 (23) was found to promote apoptosis in leukemia cell lines HL60, U937, and Kasumi-1 in a dose-dependent manner. Moreover, it was found to promote leukemia cell differentiation as evidenced by the formation of vacuoles and granules in cytoplasm. Therefore, MI-192 (23) may be effectively targeted to treat leukemia. Minami and co-workers(136) synthesized another unique benzamide derivative BG45 (24) containing a pyrazine scaffold (Figure 17). It is also a highly potent HDAC3 inhibitor (IC50 = 289 nM) exerting a high degree of selectivity over HDAC1, HDAC2, and HDAC6. BG45 (24) is also considered as a reference molecule for conducting various in vitro and in vivo experiments.
Suzuki et al.(275) synthesized 504 aryl cap containing triazole derivatives using the click chemistry approach. Out of these, 59 benzamide compounds inhibited 90% of HDAC3 activity at a dose of 10 μM. However, 48 hydroxamate derivatives inhibited 60% of HDAC3 activity at 1 μM dose. Among the 107 compounds, 11 benzamide derivatives were found to exhibit HDAC3 selectivity over HDAC1 and HDAC2. Two compounds (50 and 51, Figure 17) resulted in potent and selective HDAC3 inhibition (IC50 = 240 nM and IC50 = 260 nM, respectively) having exceptional selectivity over HDAC1, HDAC4, HDAC6, and HDAC8. The molecular docking study(275) of compound 50 with HDAC3 (PDB 4A69) suggested that this compound coordinated with the catalytic Zn2+ ion through amino and carbonyl groups (Figure 18).
Figure 18
Figure 18. Molecular docking interaction of compound 50 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.
It also formed two hydrogen bonding interactions with His134 and Gly143 with the amino group and amide group, respectively. The phenyltriazole moiety extended toward the hydrophobic tunnel of HDAC3 formed by the amino acid residues Phe144, Phe200, and Leu266. The terminal thienyl group of compound 50 showed hydrophobic interactions with Pro23 and Phe144. The triazole moiety was geometrically oriented in such a fashion that proper hydrogen bonding interaction could take place for exerting higher HDAC3 inhibition. Both these compounds were found to induce acetylation of NF-κB in HCT116 colon cancer cells evaluated through Western blot analysis. Moreover, the p53 acetylation level was not enhanced by the compounds compared to SAHA (1). These results strongly suggested that the compounds selectively inhibited HDAC3. Moreover, the compounds did not elevate α-tubulin acetylation, which is a parameter for HDAC6 inhibition. Compared to SAHA (1), both compounds exhibited better cytotoxicity against colon cancer cell line HCT116 and prostate cancer cell line PC3. Compounds 50 and 51 markedly repressed HIV-1 expression in latent HIV-1 infected OM 10.1 cells, which suggested that the HDAC3 inhibitors in combination with other anti-HIV agents might be useful in targeting HIV inhibition.
Marson et al.(276) designed and synthesized a series of heterocyclic cap group containing benzamides as potent and HDAC3-selective inhibitors. Replacement of the pyridopyrimidine cap group of the nonselective HDAC inhibitor mocetinostat/MGCD0103 (16, Figure 4) with a phenylimidazolinone moiety led to the development of a potent HDAC3 inhibitor (52, Figure 19) selective over HDAC1, HDAC2, HDAC6, and HDAC8.
Figure 19
Figure 19. Benzamide-based, potent, and HDAC3-selective inhibitors.
The corresponding (S)-phenyl analog (53, Figure 19) containing a thiazoline moiety in place of the imidazolinone scaffold was a highly potent and HDAC3-selective inhibitor (IC50 = 12 nM) maintaining more than 7-fold selectivity over the above-mentioned HDACs. The molecular docking study(276) of the thiazoline derivative 53 with HDAC3 (PDB 4A69) showed that the carbonyl group adjacent to the benzyl moiety and the amine group of the benzamide moiety coordinated the catalytic Zn2+ ion. The benzylamide linker spacer was properly accommodated by a bigger hydrophobic tunnel surrounded by amino acid residues Phe144, Phe200, and Leu266. The cap group containing phenyl and thiazoline moieties showed an interaction with Phe199. Compound 53 displayed good physicochemical properties including higher solubility as well as weak cytochrome P450 inhibitory profile. Compound 53 also showed effective cytotoxicity against various cancer cell lines, namely, A549 (IC50 = 5.78 μM), DU145 (IC50 = 6.40 μM), HCT116 (IC50 = 2.17 μM), and MCF-7 (IC50 = 5.43 μM). However, the imidazolinone derivative 52 exhibited comparatively lower cytotoxicity in HCT116 (IC50 = 18.2 μM) and MCF-7 (IC50 = 30.1 μM) without showing much cytotoxicity in the other two cell lines (IC50> 50 μM). Again, compound 53 enhanced acetylation of H3 on lysine 9 (H3K9Ac) in HeLa and Jurkat cell lines. Interestingly, compound 52 enhanced H3K9Ac in Jurkat but not HeLa cell line at the dose used. Moreover, the flow cytometry analysis revealed that compound 53 enhanced the sub-G1 DNA level in Jurkat cells for apoptosis induction. However, compound 53 induced apoptosis in the G2/M phase in the HeLa cell line. Interestingly, compound 53 also induced apoptosis in Jurkat cells by PARP degradation mediated by caspase-3.
Further, Marson and co-workers(277) reported some highly HDAC6-sparing HDAC3-selective benzamide compounds containing chiral oxazoline cap groups. Compound 54 (Figure 19) containing m-fluorophenyl substitution at the fourth position of the oxazoline group exhibited potent HDAC3 inhibition (IC50 = 24 nM) having a minimum of 10-fold selectivity over the other HDACs. Moreover, aryl substitution at the fourth or fifth position of the oxazoline moiety favored HDAC3 inhibition. The compound having 4,5-diphenyl substitution at the oxazoline scaffold (55, Figure 19) displayed the highest HDAC3 inhibition (IC50 = 6 nM) having a minimum of 18-fold selectivity over the other HDACs. Compound 54 enhanced H3 acetylation in U937 and PC3 cell lines. Nevertheless, flow cytometry analysis revealed that compound 54 increased the sub-G1 DNA content in PC-3 but not in U937 cell line. Additionally, the compounds exhibited DNA accumulation in the G0/G1 phase in U937 cells. Interestingly, compound 54 significantly reduced cyclin E expression in U937 but not in the PC-3 cell line.
Wagner and co-workers(204) structurally modified CI-994 (56, Figure 19) with various substituents and designed some benzamide derivatives. Fluoro substitution at the para position of the benzamide group of CI-994 (56, Figure 19) resulted in BRD3308 (25, Figure 19) which is a highly potent HDAC3 inhibitor (IC50 = 64 nM) maintaining about 17-fold selectivity over HDAC1 and HDAC2. The molecular docking study suggested that BRD3308 (25) had no effect on conformational changes of Leu133 at the HDAC3 active site (PDB 4A69). Both CI-994 (56) and BRD3308 (25) reduced cytokine-induced caspase-3 activity and suppressed β-cell apoptosis in rat INS-1E insulinoma cells. Moreover, CI-994 (56) and BRD3308 (25) also enhanced H3 acetylation in INS-1E cells. The inhibition of HDAC3 activity by both CI-994 (56) and BRD3308 (25) was found to protect β-cells in glucolipotoxic conditions and subsequently to protect rat and human islets. BRD3308 (25) also restored insulin secretion along with a reduction of ROS due to endoplasmic reticulum (ER) stress in INS-1E cells. Moreover, it was also found that HDAC3 (not HDAC1 and HDAC2) was markedly dysregulated in the islets of type-II diabetes patients. It was also noticed that HDAC3-selective inhibition by BRD3308 (25) did not produce thrombocytopenia, whereas HDAC1 and HDAC2 inhibition did produce such toxic effects. This indicated that HDAC3-selective inhibition by BRD3308 (25) was devoid of off-target toxicity. Therefore, HDAC3-selective inhibitors of this type might be useful not only for increasing insulin secretion but also for protecting β-cells from apoptosis, as well as overcoming β-cell glucolipotoxicity in type-II diabetes patients.
Li et al.(278) reported some indole-based arylcarboxamido benzamides as promising HDAC inhibitors. Most of these benzamides displayed potency and selectivity toward HDAC1. Interestingly, only one indole-based arylcarboxamide compound (57, Figure 19) containing a pentamethylene spacer and a p-fluoro group substituted at the benzamide group exhibited potent HDAC3 inhibitory effects (IC50 = 110 nM) with a minimum of 5-fold selectivity over HDAC1 and HDAC2, along with sparing HDAC4, HDAC6, and HDAC8 inhibition.
Hsieh et al.(279) designed a series of benzamide-derived HDAC3-selective inhibitors from pan-HDAC inhibitor AR-42 (58, Figure 19). All these compounds were designed by altering the hydroxamate moiety with a benzamide scaffold along with modification of the aryl cap group and linker function of AR-42 (58). Most of the newly designed molecules were highly potent and HDAC3-selective inhibitors over HDAC1 and HDAC2. They also established that these compounds were not effective in the alteration of tubulin acetylation as well as Notch1, which strongly suggested that these compounds were not effective as HDAC6 and HDAC8 inhibitors. The SAR analysis(279) revealed that fluoro substitution at the para position of the benzamide group yielded potent HDAC3-selective inhibitors. A pyridyl group in place of the phenyl group at the linker function yielded higher HDAC3 inhibitory potency, but HDAC3 selectivity was reduced. Nevertheless, depending on the type of aryl cap group and the related substituents, HDAC3 inhibitory activity and selectivity was found to be altered. Compounds 59 and 60 (Figure 19) were the most effective and selective HDAC3 inhibitors in this series. However, MTT assay revealed that both these compounds were moderately effective in breast cancer cell line MDA-MB-231 (IC50 ≥ 10 μM). Moreover, both the compounds were found to be highly effective in inhibiting colony and mammosphere formation. Western blot analysis further suggested that the compounds downregulated AKT phosphorylation along with β-catenin expression with an increase in H3 acetylation. At 100 mg/kg oral dose, compound 60 mimicked the suppression of HDAC3 depletion of breast tumorogenecity in MDA-MB-231-induced animal model. Therefore, such HDAC3 inhibitors may be targeted for the effective treatment of triple negative breast cancer (TNBC).
McClure et al.(280) reported substrate-driven HDAC3-selective inhibitors. The benzofuran compound with m-fluoro substitution at the benzamide moiety (61, Figure 19) yielded highly potent and 15-fold HDAC3-selective inhibitory activity (IC50 = 80 nM) over HDAC1 and HDAC2. However, 3,4-difluoro substitution at the benzamide moiety (62, Figure 19) yielded 2-fold reduction in HDAC3 inhibition (IC50 = 170 nM) compared to the earlier one, but the selectivity was improved to 34-fold. Compound 62 showed induction of NF-κB p65 and p53 acetylation level without showing any inductive effect on H3/H4 and tubulin acetylation. Also, compound 62 decreased NO production in LPS-induced RAW264.7 cells along with inhibition of high mobility group box protein 1 (HMGB-1) secretion from activated macrophage cells. Combining these observations, it is inferred that HDAC3-selective inhibition may be utilized for the treatment of inflammatory diseases. Compound 62 had the ability to reduce the nuclear localization of HDAC3, which was not observed for SAHA (1). This suggested that compound 62, due to HDAC3-selective inhibitory property, was involved in alterations of cellular localization, p53 acetylation, and regulation of gene transcription to exert anti-inflammatory responses.
Ocasio et al.(281) reported two ferrocene-based benzamide analogs with potent and HDAC3-selective inhibitory activity. Compound 63 (Figure 20A) with a tetramethylene linker/spacer between two carboxamide moieties demonstrated potent HDAC3 inhibition (IC50 = 606 nM) having a minimum of 15-fold selectivity over other HDACs. However, pojamide (64, Figure 20A) with a hexamethylene linker unit showed improved HDAC3 inhibition by more than 6.5-fold (IC50 = 90 nM) compared to compound 63. Again, compound 64 possessed more than 12-fold HDAC3 selectivity over the other HDACs.
Figure 20
Figure 20. (A) Ferrocene-based benzamides as potential HDAC3 inhibitors. (B) Molecular docking interaction of compounds 63 and 64 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow. (C) 2-Aminobenzamides as effective HDAC3 inhibitors. (D) Effective HDAC3-selective proteolysis targeting chimera (PROTAC) containing benzamide as ZBG.
Both these compounds were docked into the active site of HDAC3 (PDB 4A69). The free amine group of pojamide (64, Figure 20B) coordinated the catalytic Zn2+ ion. It also displayed effective hydrogen bonding interactions with His134 and Asp170. Moreover, the adjacent amide group of the phenyl group formed a hydrogen bonding interaction with the carbonyl function of Gly143. The other amide group adjacent to the ferrocenyl group formed a hydrogen bonding interaction with the carbonyl group of Asp93. The docked structure of compound 63 was slightly different from that of pojamide (64, Figure 20B). Due to the tetramethylene carbon unit, it did not extend properly toward the Zn2+ ion. Therefore, the ligand-binding interactions were slightly shifted. The free amine group, instead of zinc-binding, formed a hydrogen-bonding interaction with Gly143. The carbonyl group associated with the benzamide scaffold interacted with the Zn2+ ion. The differences in the interaction clearly pointed out the better activity and selectivity of pojamide (64) over compound 63. It was also interesting to note that due to steric clashes with Tyr100, Lys33, and the ferrocenyl moiety, pojamide (64) did not bind effectively to the active site of HDAC8 (PDB 1T69). This might be the reason for HDAC3 selectivity of the ferrocenyl compounds. It was interesting to note that pojamide (64) showed equipotent HCT116 cytotoxicity (GC50 = 8.6 μM) compared to HDAC3-selective inhibitor RGFP966 (22) (GC50 = 8.9 μM). Pojamide (64) also increased the acetylated H4K12 level, but compound 63 did not show any effect. Again, pojamide (64) exhibited 90% HCT116-cellular invasion. Nevertheless, pojamide (64) along with sodium nitroprusside reduced the pH2AX level with DNA damage, which may be fruitful in combating colon cancer.
Trivedi and co-workers(282) reported a series of 2-aminobenzamides as effective HDAC3 inhibitors. The compounds were designed by structural modifications of both CI-994 (56) and BG45 (24). Three compounds (65–67, Figure 20C) were found to be more than 5-fold HDAC3-selective over HeLa nuclear extract (rich in HDAC1 and HDAC2). Apart from that, these three compounds exhibited better HDAC3 inhibition compared to both BG45 (24) and CI-994 (56). The SAR analysis revealed that aminophenyl or aminobenzyl group attached to the pyrazine moiety is necessary for imparting HDAC3 inhibitory potency. Compound 65 showed better antiproliferation activity against B16F10 melanoma and HeLa cell lines compared to CI-994 (56) and BG45 (24). Compound 65 also showed the highest apoptosis as evidenced by annexin V FITC/PI assay in B16F10 melanoma. Moreover, the cell cycle analysis suggested that compound 65 significantly arrested the G2/M phase cell growth in the B16F10 cell line.
A series of HDAC targeting proteolysis targeting chimeras (PROTACs) containing a benzamide ZBG was synthesized by Cao and co-workers.(283) Only one HDAC-PROTAC (68, Figure 20D) exhibited HDAC3 selectivity (IC50 = 1100 nM) over HDAC1 (IC50 = 3600 nM) and HDAC2 (IC50 = 4200 nM). Compound 68 mediated the degradation of HDAC3 (DC50 = 3200 nM). It was also found to trigger E3 ligase-mediated ubiquitination and subsequent HDAC3 degradation regulated by proteasome. Compound 68 did not show any significant effect on pro- and anti-inflammatory gene transcription. However, the combination of both compound 68 and cereblon (CRBN) ligand pomalidomide was found to downregulate NF-κB p65 in RAW264.7 macrophages.
4.3. Hydrazide-Based HDAC3-Selective Inhibitors
Wang et al.(109) reported a series of benzoylhydrazide derivatives as potent and selective HDAC3 inhibitors. The p-bromo analog (69, Table 4) exhibited potent HDAC3 inhibition (IC50 = 190 nM) with a minimum of 2.5-fold selectivity over the other HDACs.
Table 4. Benzoylhydrazides as Potent and Selective HDAC3 Inhibitors
| IC50 (nM) | |||||||
|---|---|---|---|---|---|---|---|
| compd | R1 | R2 | HDAC1 | HDAC2 | HDAC3 | HDAC6 | HDAC8 |
| 69 | Br | n-butyl | 460 | 1330 | 190 | 9090 | 2830 |
| 70 | OMe | n-butyl | 1910 | 2520 | 430 | a | a |
| 71 | t-butyl | n-butyl | 190 | 1040 | 70 | 6830 | 490 |
| 72 | Br | n-propyl | 1700 | 3880 | 220 | 4630 | a |
a
Not determined.
A compound with methoxy substitution at the R1 position (70, Table 4) exhibited potent HDAC3 inhibition (IC50 = 430 nM) with about 4.5-fold HDAC3 selectivity over the other HDACs. Interestingly, the t-butyl analog (71, Table 4) yielded the maximum HDAC3 inhibition (IC50 = 70 nM) with more than 2.5-fold HDAC3 selectivity over the other HDACs. Again, the n-propyl analog (72, Table 4) exhibited potency similar to that of the corresponding n-butyl analog (69, Table 4) but the n-propyl analog (72, Table 4) was about 8-fold HDAC3 selective over the other HDACs. Compound 69 strongly inhibited the deacetylation at H4K5 in the HCT116 cell line but did not exhibit any effect on α-tubulin acetylation. It was found to increase the acetylation level of p53 in HCT116 cell line. It also induced acetylation of H2B, H3, and H4. In cell cycle analysis, compound 69 was found to block G2/M phase in a dose-dependent manner. It also activated the p53 and Rb tumor suppressor pathways and suppressed the MYC, MYNC, and KRAS oncogenic pathways. Therefore, inhibitors of this type might be useful in anticancer therapy.
McClure and co-workers(284) reported some hydrazide derivatives as potential HDAC3 inhibitors with promising cytotoxicity against acute myeloid leukemia (AML) compared to solid tumors. The SAR analysis suggested that compounds with smaller alkyl substitution at the hydrazide function resulted in better HDAC3 selectivity compared to the compounds with longer alkyl functions, though all showed higher affinity toward HDAC3. Interestingly, the alkyl chain length should possess three to four carbon units to exert higher HDAC3 inhibition as well as selectivity. Compound 73 (Figure 21) resulted in potent and HDAC3-selective inhibition (IC50 = 1 nM) having a minimum of 12-fold selectivity over HDAC1 and HDAC2 and selectivity for AML over HEK293.
Figure 21
Figure 21. Arylhydrazides as potent and HDAC3-selective inhibitors.
However, an extension of alkyl chain length further by one carbon unit, resulting in n-butyl analog 74 (Figure 21) led to a 4-fold decrease in HDAC3 inhibition (IC50 = 3.7 nM) though compound 74 exhibited a minimum of 16-fold selectivity over HDAC1 and HDAC2 and for AML over HEK293. Elimination of the unsaturated linker from compound 73 resulted in compound 75 (Figure 21), which had reduced HDAC3 inhibitory activity (IC50 = 3.5 nM) with a minimum of 4-fold selectivity over HDAC1 and HDAC2. The same phenomenon was observed for compound 76 (Figure 21), which was also 2-fold HDAC3-selective over the other HDACs. The molecular docking study revealed that compound 73 perfectly fitted into the HDAC3 active site (PDB 4A69). The propylhydrazide moiety entered a narrow tunnel at the active site, whereas SAHA (1) was found to fit into the active site in a completely different orientation. Compound 73 was further evaluated against an array of leukemia and myeloma cell lines. Compound 73 was found to be extremely cytotoxic against the leukemia cell lines, such as MV4-11 (EC50 = 36.37 nM), Molm14 (EC50 = 76.64 nM), and K562 (EC50 = 2160 nM) but comparatively inactive in multiple myeloma cell line RS4-11 (EC50> 10000 nM). Compounds 73, 75, and 76 (Figure 21) enhanced the level of acetylated histones H3 and H4 compared to SAHA (1) as evidenced by the Western blot analysis. Therefore, hydrazide-based HDAC3 inhibitors of this type might prove efficient in the treatment of AML.
Recently, Li et al.(285) designed some new indole cap containing HDAC3 inhibitors selective over HDAC1, HDAC2, and HDAC6. The carboxamidobenzyl derivative having an n-propylhydrazide moiety (77, Figure 22) resulted in potent HDAC3 inhibition (IC50 = 8.5 nM) with a minimum of 7.5-fold selectivity over HDAC1, HDAC2, and HDAC6.
Figure 22
Figure 22. Indole cap containing hydrazides as potent and HDAC3-selective inhibitors.
However, an increase in the alkyl side chain, that is, in the butylhydrazide function, led to the development of compound 78 (Figure 22), which is a 2-fold less potent HDAC3 inhibitor (IC50 = 16.5 nM) than the former one. Compound 78 maintained a minimum of 3-fold HDAC3 selectivity over these HDACs. The SAR observation revealed that a linear alkyl chain length with three to four carbon units should be optimum for maintaining potent HDAC3 inhibitory activity as well as selectivity. Keeping the n-propylhydrazide moiety unaltered, alteration of the linker spacer moiety on HDAC3 inhibition was also monitored. Replacement of the carboxamidobenzyl moiety (compound 77) with carboxamidophenyl group (79, Figure 22) increased HDAC3 inhibition 6-fold (IC50 = 1.4 nM) with a minimum of 7-fold selectivity over the other class I HDACs along with sparing class II HDAC inhibition. Similarly, the carboxamido moiety with long chain linear alkyl functions such as n-pentyl (80, Figure 22), n-hexyl (81, Figure 22), and n-heptyl (82, Figure 22) resulted in highly potent and HDAC3-selective inhibition with IC50 values of 12.4 nM, 5.2 nM, and 12.1 nM, respectively. The molecular docking study of compound 77 (Figure 23) with the HDAC3 catalytic site (PDB 4A69) suggested that the carbonyl function adjacent to the hydrazide moiety coordinated the catalytic Zn2+ ion.
Figure 23
Figure 23. Molecular docking interaction of compound 77 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.
Moreover, compound 77 was also found to accept hydrogen bonds from the side chain of amino acid Tyr298. One amide function of the hydrazide moiety donated a hydrogen bond to Gly143, whereas the other amide function of that moiety donated a hydrogen bond to Asp170 and simultaneously accepted a hydrogen bond from His135. The two other amide functions were found to donate hydrogen bonds to Asp93 at the HDAC3 catalytic site, whereas the indole amide function donated hydrogen bonds to backbone amino acid Arg265. It was noticed that compound 79 inhibited MV4-11 leukemia cell line (EC50 = 34.7 nM) and prostate cancer PC-3 cell line (EC50 = 351 nM) in lower concentrations. The Western blot analysis revealed that compound 79 cleaved pro-caspase-3 with a subsequent enhancement of cleaved caspase-3 as well as cleaved PARP, indicating its ability to modulate caspase-dependent apoptosis in the MV4-11 cell line. Moreover, the cell cycle analysis suggested that compound 79 induced sub-G1 cellular arrest in the MV4-11 cell line and G2/M cellular arrest in the PC-3 cell line. Further, compound 79 degraded p53 and subsequently depleted the antiapoptotic proteins c-FLIP and XIAP in the MV4-11 cell line, suggesting the induction of cellular apoptosis.
Li et al.(286) reported some hydrazide compounds depending on the scaffolds of panobinostat (3). Almost all these compounds were found to be potent and selective toward HDAC3 compared to HDAC1, -2, and -6. Initially, the hydroxamate function of panobinostat (3) was replaced with n-propylhydrazide moiety and the amide function of the linker moiety was substituted. Compound 83 (Figure 24) bearing a t-butoxy group displayed potent HDAC3 inhibition (IC50 = 16.8 nM) maintaining a minimum of 10-fold selectivity over HDAC1, HDAC2, and HDAC6.
Figure 24
Figure 24. Panobinostat-based hydrazides as potent and HDAC3-selective inhibitors.
Omission of the t-butoxy substitution at the amide group of linker function led to the discovery of compound 84 (Figure 24), which is about 60-fold more potent (IC50 = 0.3 nM) than 83. It also maintained a minimum of 18-fold HDAC3 selectivity over other HDACs. However, esterification (85, Figure 24) reduced the HDAC3 inhibition drastically, though this compound was also HDAC3 selective. Therefore, it may be postulated that alkyl substitution at the hydrazide moiety is responsible for HDAC3 inhibitory potency and selectivity. Replacement of the indolylethyl group of panobinostat (3) with a benzyl group produced compound 86 (Figure 24), which was a potent HDAC3 inhibitor (IC50 = 6.1 nM), but it showed only 2.5-fold HDAC3 selectivity over HDAC1. However, compound 87 (Figure 24) including a di-n-propyl group instead of an n-propyl group substituted at the terminal amide function resulted in more or less similar potency and selectivity compared to compound 83. Importantly, compound 84 was also found to be a more potent and HDAC3-selective inhibitor than both panobinostat (3) (IC50 = 2.1 nM) and entinostat (15) (IC50 = 77.18 nM). Compound 84 displayed anticancer activity that is p53- and FLT3-status dependent. In wt-p53 FLT-ITD cell line MV4-11, it was found to cleave the pro-caspase 3 and induce apoptosis. It indirectly inhibited the FLT3 pathway through downregulation of FLT3, STAT5, and pERK, which may be effective in combating AML. It also reduced antiapoptotic proteins c-FLIP and XIAP followed by cleavage of pro-caspase 3. Again, compound 84 was found to induce autophagic mechanisms in p53 MV4-11 cells. Moreover, the combination of compound 84 and bortezomib synergistically triggered the pro-caspase 3 cleavage. Noticeably, compound 84 was less genotoxic than panobinostat (3). Further, the bioavailability and pharmacokinetic profile of compound 84 was better than those of panobinostat as evidenced by better half-life (t1/2) and higher AUC values.
Xiao et al.(287) reported some HDAC3-specific PROTACs based on compound 88 (Table 5), which is also a potent and HDAC3-selective inhibitor (IC50 = 13 nM).
Table 5. HDAC Inhibitory Profile of New PROTACs
| IC50 (nM) | |||||
|---|---|---|---|---|---|
| compd | m | n | HDAC1 | HDAC2 | HDAC3 |
| 88 | 72 | 82 | 13 | ||
| 89 | 2 | 90 | 400 | 38 | |
| 90 | 5 | 650 | 1550 | 350 | |
| 91 | 7 | 1500 | 1420 | 550 | |
Among these CRBN-based PROTACs with PEG linkers, compound 89 (Table 5) exhibited potent HDAC3 inhibition (IC50 = 38 nM) with selectivity over HDAC1 and HDAC2. However, the HDAC3 inhibitory potency was reduced by 10–15-fold for VHL-based PROTACs. Compounds 90 and 91 (Table 5) displayed good HDAC3 inhibition having more or less similar selectivity pattern compared to compound 89. Importantly, compound 90 was found to induce HDAC3 degradation in MDA-MB-468 cells in a dose-dependent fashion (DC50 = 42 nM) without showing any significant changes in protein levels of HDAC1, -2, and -6. Nevertheless, HDAC3 degradation induced by compound 90 was also time-dependent (70% HDAC3 was degraded within 8 h). Apart from that, compound 90, in a dose-dependent manner, enhanced histone acetylation moderately compared to CRBN-based PROTACs. It reflected the selective pattern of HDAC3 degradation conferred by compound 90.
4.4. Modified Benzamide-Based HDAC3-Selective Inhibitors
A series of 2-substituted modified benzamides were designed and synthesized as potent and highly selective HDAC3 inhibitors by Liu and co-workers(288) by using parallel medicinal chemistry (PMC) libraries. Compound 92 (Figure 25) bearing a 2-methylaminobenzamide scaffold resulted in potent HDAC3 inhibition (IC50 = 41 nM) having 366-fold selectivity over HDAC1 sparing other HDACs.
Figure 25
Figure 25. Modified benzamide derivatives as potent and highly HDAC3-selective inhibitors.
Modification of the 2-methylaminobenzamide scaffold with the 2-methylthiobenzamide group led to the development of the most selective inhibitor (93, Figure 25) of this series. It was also a highly potent HDAC3-selective inhibitor (IC50 = 29 nM) with 690-fold HDAC3 selectivity over HDAC1. It spared HDAC2 along with HDAC4, -5, -6, -7, -8, and -9 as well as maintaining a minimum of 69-fold selectivity over HDAC10 and HDAC11. On the other hand, the respective cyclopropyl derivative (94, Figure 25) was also a highly potent and selective HDAC3 inhibitor (IC50 = 170 nM). Keeping the methylthiobenzamide moiety unaltered, modification of the terminal naphthyl group with 2-methoxy-3-quinolinyl moiety also yielded a potent and HDAC3-selective inhibitor (95, Figure 25). Interestingly, compound 93 and other 2-substituted modified benzamide analogs are supposed to bind the catalytic Zn2+ ion of HDAC3 in a monodentate fashion. However, the HDAC3 selectivity of these compounds is probably due to the induced fitting of the 2-substituents in the binding pocket formed by the flipping of the catalytic Tyr305 residue.
4.5. Ethylketones as HDAC3-Selective Inhibitors
Kinzel et al.(289) reported some ketone-based selective class I HDAC inhibitors. Compound 96 (Figure 26) containing an oxazole ring and a dimethylaminoisopropyl moiety was a potent HDAC3 inhibitor (IC50 = 0.6 nM). Compound 96 also displayed a minimum of 6-fold HDAC3 selectivity over HDAC1 (IC50 = 3.5 nM) and HDAC2 (IC50 = 5.3 nM).
Figure 26
Figure 26. Ethylketones and nicotinamides as effective HDAC3 inhibitors.
Modification of the dimethylaminoisopropyl group with a 5-thiazolyl moiety, the oxazole ring with an imidazole ring, and the ethylcarbonyl group with methylaminocarbonyl function produced compound 97 (Figure 26) showing a 40-fold loss in HDAC3 inhibition (IC50 = 24 nM) compared to compound 96. However, compound 97 was more HDAC3-selective over HDAC1 and HDAC2 compared to 96. Again, further modification of compound 97 with 4-pyrazolylphenyl and indole-3-yl ethyl groups (98, Figure 26) decreased the HDAC3 inhibition (IC50 = 42 nM), but the HDAC3 selectivity was increased. Similar highly selective molecules were developed when the 4-pyrazolylphenyl moiety of compound 98 was replaced with a p-dimethylaminophenyl group (99, Figure 26). Cyano substitution at the sixth position of the indole moiety of compound 99 yielded highly potent HDAC3-selective inhibitor 100 (IC50 = 26 nM). It was interesting to observe that the compounds with methylaminocarbonyl moiety resulted in less potent but more HDAC3-selective inhibitors compared to compounds with the ethylcarbonyl moiety. Compound 100 (Figure 26), the most HDAC3-selective inhibitor in this series (selectivity a minimum of 50-fold) also showed good stability in both plasma and hepatocytes of mouse and human.
4.6. Nicotinamides as HDAC3-Selective Inhibitors
Hamoud and co-workers(290) recently designed and synthesized some N-(4-(2-arylidenehydrazine-1-carbonyl) phenyl) nicotinamide derivatives as potent and HDAC3-selective inhibitors. Pyridine being a bioisostere of benzene, the benzamide ZBG group was replaced with the m-pyridyl carboxamide ZBG function. The N-acylhydrazone moiety was selected as the linker function linking the aryl or heteroaryl surface recognition cap functionality and the m-pyridyl carboxamide ZBG. Compound 101 (Figure 26) having a p-tolyl cap group demonstrated potent HDAC3 inhibition (IC50 = 694 nM) with about 7-fold selectivity over pan-HDACs. Replacement of the cap group with o-nitrophenyl group (102, Figure 26) slightly decreased the activity (IC50 = 887 nM), but the selectivity remained almost the same. Compound 101 resulted in the highest anticancer activity against B16F10 melanoma (IC50 = 4.66 μM), whereas compound 102 yielded the best antiproliferation activity against MCF7 breast cancer (IC50 = 7.90 μM) without any toxicity to normal HEK-293 cell line. The best active compound 101 was subjected to molecular docking with HDAC3 enzyme (PDB 4A69). The carbonyl group adjacent to the pyridyl moiety coordinated the Zn2+ ion at the active site (Figure 27).
Figure 27
Figure 27. Molecular docking interaction of compound 101 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line; hydrogen bonding interactions are shown in dotted green arrow; π–π stacking interactions are shown in dotted blue line.
Also, the carbonyl group accepts a hydrogen bond from active site residues His134 and His135. Moreover, the adjacent amide group formed a hydrogen bonding interaction with Gly143. The N-benzoylhydrazone linker fitted properly into the active site hydrophobic channel having a π–π stacking interaction with His172. Also, the p-tolyl cap group formed a π–π stacking interaction with Phe199 (Figure 27). These compounds passed Lipinski’s criteria for being drug-like candidates and showed low blood–brain barrier (BBB) permeability with no interaction with CYP2D6.
4.7. HDAC3-Selective Inhibitors Derived from Natural Compounds
Wang et al.(291) reported some thailandepsin analogs as potent HDAC3 inhibitors highly selective over the other HDACs. Romidepsin/FK228 (18, Figure 28) was a highly potent HDAC3 inhibitor (IC50 = 18 nM), whereas thailandepsin A (103, Figure 28) showed about a 5-fold less potent HDAC3 inhibition (IC50 = 87 nM).
Figure 28
Figure 28. Thailandepsin analogs and natural products as potent and HDAC3-selective inhibitors.
However, it was also a highly HDAC3-selective inhibitor over the other HDACs. Interestingly, thailandepsin B (104, Figure 28) with a slight structural difference (presence of butyl function in place of methylthioethyl group) was 5-fold better than thailandepsin A (103, IC50 = 23 nM) and comparable to romidepsin/FK228 (18). However, the corresponding reduced compounds produced nonselective HDAC inhibition. The NCI-60 anticancer drug screening and COMPARE analysis revealed that all the compounds possessed a broad spectrum of antitumor efficacy against diverse cancer cell lines. However, their efficacy was better in colon cancer, renal cancer, and melanoma than in leukemia. Thailandepsin A (103) was more potent in most of the cancer cell lines in terms of GI50 value. However, in terms of TGI and LC50 values, it was only found better in particular cell lines, namely, HCC-2998 colon cancer, A498, and RXF393 renal cancer, as well as UACC-62 and LOXIMVI melanoma cell lines.
Li et al.(292) designed, synthesized, and biologically screened some largazole analogs as potent HDAC3 inhibitors selective over HDAC1, HDAC2, and HDAC9. Largazole (105, Figure 28), a naturally occurring macrocyclic depsipeptide was reported by Taori and co-workers(293) as a potential anticancer agent that was further synthesized, biologically screened, and extensively studied by various group of researchers.(294−298) Largazole (105) was a potent and selective HDAC1 inhibitor (IC50 = 146 nM) having a minimum of 4-fold selectivity over the other HDACs.(292) Interestingly, elimination of the heptacarbonyl function of largazole to form a free thiol group as well as modification of the 4-methylthiazoline function with a tetrazolylmethyl function led to the development of compound 106 (Figure 28), which was a highly potent and HDAC3-selective inhibitor (IC50 = 31 nM) with a minimum of 3-fold selectivity over the other HDACs.
5. Dual HDAC1/3 and HDAC3/6 Selective Inhibitors
ARTICLE SECTIONS
It was interesting to observe that a number of compounds have both potent HDAC3 and HDAC1 inhibitory activity but selectivity over HDAC2 or other HDACs. Nevertheless, many such potential dual HDAC1/3 inhibitors have an effective role in combating various cancers and related diseases. A few compounds also exert dual HDAC3/6 selective inhibition. In this context, it should be mentioned that such compounds may also be utilized as a starting compound for designing selective HDAC3 inhibitors. Effective modification of these molecules either through intuitive design or by robust SAR and molecular modeling analysis may be able to generate newer selective HDAC3 inhibitors. Therefore, in this section, such dual HDAC1/3 and HDAC3/6 selective inhibitors have been discussed.
5.1. Hydroxamates as Dual HDAC1/3 Selective Inhibitors
Zhang and co-workers(300) reported an indole-based N-hydroxycinnamide compound (108, Figure 29, Table 6) exhibiting potent dual HDAC1/3 inhibitory activity selectively over HDAC2 and HDAC6.
Figure 29
Figure 29. (A) Hydroxamate-based dual HDAC1/3 inhibitors. (B) Benzamide-based dual HDAC1/3 inhibitors. (C) Hydrazide-based dual HDAC1/3 inhibitors. (D) Romidepsin-based dual HDAC1/3 selective inhibitors. (E) Dual HDAC3/6 selective inhibitors.
Table 6. Compounds Having Dual HDAC1/3 and HDAC3/6 Inhibitory Activity
| IC50 (nM) | |||||||
|---|---|---|---|---|---|---|---|
| compd | R | R′ | HDAC1 | HDAC2 | HDAC3 | HDAC6 | HDAC8 |
| 108(300) | -CH(n-propyl)2 | OMe | 390 | 1420 | 280 | 940 | |
| 109(270) | p-OMePh | OMe | 17.5 | 59.5 | 7.1 | 87 | |
| 110(165) | p-ClPh | H | 11.8 | 498.1 | 3.9 | 308.2 | |
| 111(165) | p-FPh | H | 16.7 | 457 | 3.5 | 101.7 | |
| 112(165) | p-OMePh | H | 6 | 413.6 | 3.2 | 185.6 | |
| 113(301) | 5-(dimethylamino)naphthalene-1-sulfonyl | – | 24.7 | 106.7 | 24.4 | 365.9 | |
| 114(301) | 2-methoxy-PhNHCO | 4.8 | 19.5 | 5.9 | 294.2 | ||
| 115(302) | p-OMeBnz | 250 | 1800 | 120 | 720 | ||
| 116(303) | H | 98 | 330 | 97 | a | 1900 | |
| 117(304) | Me | 150 | 760 | 370 | 5000 | ||
| 118(278) | p-OMePhCO- | indole-3-ylmethyl | 58.6 | 296 | 42.9 | ||
| 119(109) | -NMe2 | n-butyl | 230 | 880 | 120 | 9570 | 720 |
| 120(109) | t-butyl | n-butyl | 190 | 1040 | 70 | 6830 | 490 |
| 121(109) | p-OMePhCO- | n-pentyl | 29.8 | 332.1 | 10.9 | >100000 | |
| 122(286) | Boc | 28.8 | 278.6 | 12.6 | >50000 | ||
| 123(286) | H | 29.4 | 107.5 | 19.9 | >50000 | ||
| 124(286) | -NHBnz | 15.8 | 67.5 | 6.12 | >50000 | ||
| 125(286) | -OBnz | 56.3 | 174.6 | 24.8 | >50000 | ||
| 126(305) | SH(CH2)2CH═CH- | i-Pr | 2.2 | 36.6 | 9.8 | 459 | 2550 |
| 127(305) | SH(CH2)2CH═CH- | H | 2.8 | 45 | 7.7 | 331 | 3550 |
| 128(306) | -CO(CH2)6CO- | 896 | 1130 | 34 | 2.6 | 1260 | |
a
97% at 10 μM.
Compound 108 (Figure 29A, Table 6) demonstrated better antiproliferative efficacy compared to SAHA (1) in a diverse set of cancer cell lines including U937, PC3, A549, ES-2, HCT116, and MDA-MB-231. In a U937 xenograft model, compound 108 displayed promising in vivo tumor growth inhibition (TGI = 53%, T/C = 42%) with no significant loss of body weight and no toxicity in liver and spleen. Replacement of the di-n-propyl function of compound 108 with a p-methoxyphenyl group led to the discovery of compound 109 (Figure 29A, Table 6), which was also a highly potent dual HDAC1/3 selective inhibitor.(270) It also showed better antiproliferative activity compared to SAHA (1) when evaluated in 5 different cancer cell lines (namely, MOLT-4, HEL, K562, HeLa, and PC-3). A slight modification of compound 109 resulted in some highly potent dual HDAC1/3 selective inhibitors (110–112, Figure 29A, Table 6).(165) Due to a high degree of structural similarity with compounds 108 and 109, these compounds (110–112) also displayed better cytotoxicity in various cancer cell lines (namely, U937, K562, HEL, HL60, MDA-MB-231, PC-3, MCF-7, HCT116, and A549) compared to SAHA (1). These compounds (110–112) significantly enhanced the level of acetylated histones H3 and H4. Compounds 110 and 111 dose-dependently induced 61.76% and 64.25% cellular apoptosis, respectively, in the U937 cell line, which was better than SAHA (1) (26.83%). Compound 110 exhibited potent oral antitumor efficacy of 55.10% in a xenograft model of female BALB/c-nu mice.
In another study, Zhang and co-workers(301) reported some hydroxamates as effective HDAC inhibitors. Compound 113 (Figure 29A, Table 6) containing a 5-(dimethylamino) naphthalene-1-sulfonyl group at the cap position displayed effective HDAC1/3 dual inhibitory activity. Replacement of this group with 2-methoxyphenylaminocarbonyl function (114, Figure 29A, Table 6) produced a 5-fold improvement of both HDAC1 and HDAC3 inhibition. Both of these compounds exerted dual HDAC1/3 inhibition that was selective over HDAC2 and HDAC6. These compounds also exhibited potent cytotoxicity against various cancer cell lines, namely, U937, K562, HL60, MCF-7, MDA-MB-231, and PC3. Compound 113 (Figure 29A) exhibited 53.57% tumor growth inhibition in a U937 cell-based xenograft model, which is better than SAHA (1) (24.97%), at 100 (mg/kg)/day dose. It also showed effective HDAC inhibition with enhanced tubulin acetylation level. Compound 113 also reduced the level of p-Erk and c-Raf proteins in the U937 cell line with a decrease in pAKT level.
Abdelkarim and co-workers(302) designed, synthesized, and evaluated some amine-based HDAC inhibitors. Compound 115 (Figure 29A) containing an indole group attached to the p-methoxybenzyl function demonstrated potent dual HDAC1/3 inhibitory efficacy selectively over HDAC2 and HDAC8. Taha et al.(303) reported a tetrahydroisoquinoline-based hydroxamate derivative with hexamethylene group (116, Figure 29A) that showed dual HDAC1/3 inhibitory activity selectively over other HDAC isoforms.
5.2. Benzamides as Dual HDAC1/3 Selective Inhibitors
Keeping the linker moiety unaltered, Chou et al.(304) modified the structure of SAHA (1) by replacing the phenyl cap group with a p-tolyl group and the hydroxamate ZBG group with a benzamide moiety to produce the pimelic diphenylamide HDAC inhibitor (117, Figure 29B). Compound 117 was found to be a potent HDAC1/3 inhibitor selective over other HDAC isoforms (Table 6) sparing HDAC4, -5, and -7 (IC50 > 180 μM). Xu et al.(220) further established that compound 117 not only induces H3 histone acetylation but also specifically binds to HDAC3 to activate the expression of FXN gene as well as increase the level of frataxin protein in Friedreich’s ataxia (FRDA). Li et al.(278) reported an indole-based arylcarboxamido benzamide derivative (118, Figure 29B, Table 6) having potent dual HDAC1/3 inhibitory activity selective over HDAC2.
5.3. Hydrazides as Dual HDAC1/3 Selective Inhibitors
A benzoylhydrazide derivative containing an n-butyl group attached to the hydrazide function and a dimethylamino group substituted at the para position of the phenyl ring was found to be potent dual inhibitor of HDAC1/3 inhibitor (119, Figure 29C, Table 6) selective over HDAC2, HDAC6, and HDAC8.(109) A t-butyl group in place of the dimethylamino function produced an equipotent dual HDAC1/3 inhibitor (120, Figure 29C, Table 6) selective over other HDACs. Compound 119 was found to exert potent cytotoxicity against cancer cell lines HepG2 (IC50 = 1.5 μM), HCT116 (IC50 = 3.5 μM), MDA-MB-231 (IC50 = 7.2 μM), and HCC1957 (IC50 = 35.9 μM). Similarly, an indole cap containing benzoylhydrazide derivative (121, Figure 29C, Table 6) with an n-pentyl group attached to the hydrazide function demonstrated highly potent dual HDAC1/3 inhibitory activity selective over HDAC2 and HDAC6.
Li et al.(286) reported a series of para-substituted benzoylhydrazide derivatives where the hydrazide function was attached to the n-propyl group. The 2-methyl-indole-3-ylethyl derivatives (122 and 123, Figure 29C, Table 6) were highly potent dual inhibitors of HDAC1/3 selective over HDAC2 and HDAC6. Replacement of the 2-methyl-indole-3-ylethyl function with both aminobenzyl and methoxybenzyl groups yielded highly potent dual inhibitors of HDAC1/3 selective over HDAC2 and HDAC6 (124 and 125, Figure 29C, Table 6).
5.4. Romidepsin-Based Dual HDAC1/3 Selective Inhibitors
5.5. Dual HDAC3/6 Selective Inhibitors
Soumyanarayanan and co-workers(306) reported a hydroxamate derivative (128, Figure 29E, Table 6) having a unique dual HDAC3/6 selectivity profile over other HDACs. The molecular docking study suggested that due to the orientation of Asn197 residue, there is a preferable conformation of the loop to interact with compound 128. In the case of HDAC1 and HDAC2, there is a glutamic acid residue in place of Asn197 of HDAC3. This suggests the reason behind compound 128 being more selective toward HDAC3. Two additional amino acid residues, Asp675 and His676 (not present in HDAC1, -2, and -3) are observed in the loop of HDAC6 that provides the loop more flexibility to effectively interact with compound 128. This may be the reason for the exceptional potency of compound 128 toward HDAC6. Apart from exerting potential cytotoxicity against breast cancer cell lines MDA-MB-231 (EC50 = 6.3 μM) and MCF-7 (EC50 = 7.3 μM), compound 128 also resulted in potent cytotoxicity against multiple myeloma cell lines KMS-12BM (EC50 = 7.6 μM), H929 (EC50 = 4.6 μM), and OPM2 (EC50 = 7.9 μM) and acute myeloid leukemia cell line MOLM14 (EC50 = 2.8 μM). Compound 128 also responded well in the apoptosis assay in MDA-MB-231 cell line. The levels of histone H3 acetylation as well as tubulin acetylation were found to be enhanced markedly by treatment with compound 128, suggesting the potency toward both HDAC3 and HDAC6.
6. Future Perspectives
ARTICLE SECTIONS
In this Perspective, the role of HDAC3 in various disease conditions (cancer, inflammation, rheumatoid arthritis, neurodegenerative and CNS disorders, cardiovascular diseases, diabetes, and parasitic and viral infection) has been discussed in detail. A variety of HDAC3 inhibitors such as hydroxamates, benzamides, and modified benzamides, as well as hydrazides, has also been discussed in regards to their HDAC3 inhibitory potency and selectivity over other HDACs. A number of results have established HDAC3 as a potential biomolecular target for design and development of selective HDAC3 inhibitors to combat these disease conditions. Though it has been established that HDAC3 is a potential therapeutic target to combat multiple disease conditions, less attention has been paid to strategies for designing HDAC3-selective inhibitors. In this context, it was noticed that only a few molecular modeling studies have been performed on the existing HDAC3 inhibitors. Probably, the lack of availability of both active and HDAC3-selective inhibitors may be responsible for hindering the drug discovery processes. However, the strategies for designing HDAC3 inhibitors are mostly confined to either intuitive design or enzyme–ligand interactions. Earlier, our group performed a QSAR/QAAR analysis on the available benzamide-derived HDAC3 inhibitors to acquire knowledge linking the important structural and physicochemical aspects of the compounds and the respective bioactivity.(307) A total of 24 models were developed: 8 models developed on HDAC3 inhibitory activity, 8 models constructed on HDAC3 selectivity over HDAC1, and 8 models developed on HDAC3 selectivity over HDAC2. Regarding these QSAR models on HDAC3 inhibitory activity, it was noticed that the steric features and polar character of these molecules may be necessary for improving HDAC3 inhibition. As far as the HDAC3 inhibitory activity over HDAC1 is concerned, it was observed that the benzamide moiety along with smaller electron withdrawing fluorine atom may be crucial for maintaining the HDAC3 selectivity. However, the molecular size and shape as well as less polarity and less hydrophobicity are crucial factors for retaining HDAC3 selectivity over HDAC2. Our group further performed(308) a robust molecular modeling technique (3D-QSAR, CoMFA, and CoMSIA, as well as Bayesian classification) on 113 benzamide-based HDAC3 inhibitors. This study further justified and validated our earlier observation(307) that the benzamide moiety along with electron withdrawing fluorine substitution may attribute some favorable steric effect for enhancing HDAC3 inhibition and selectivity. This study also demonstrated that the hydrophobicity and steric character at the linker moiety favor activity. The activity is reduced whenever groups of these types are substituted at the cap position and at the terminal zinc binder moieties. Nevertheless, the amide function is found to be responsible for Zn2+ chelation. The free amino group of the benzamide scaffold may act as a hydrogen bond donor feature. Apart from such modeling techniques, various other computational methodologies (ligand-based and structure-based) may be taken into consideration for designing more active and selective HDAC3 inhibitors. Apart from that, the crystal structure of HDAC3 will also help to reveal the important ligand–receptor interactions essential for both the activity and the selectivity. Therefore, not only the ligand-based and structure-based design strategies, but also the intuitive design strategies may be beneficial for the drug discovery processes related to HDAC3. Extensive studies have been made on the molecular mechanisms on HDAC3 inhibitors. These studies are still going on. However, there is a lack in the discovery of novel potential and HDAC3-selective inhibitors. This Perspective, in a nutshell, provides a thorough idea not only about the role of HDAC3 in disease conditions but also about a diverse set of HDAC3-selective inhibitors. This will hopefully benefit researchers to identify potential HDAC3-selective inhibitors.
Author Information
ARTICLE SECTIONS
- Tarun Jha - Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, India;
https://orcid.org/0000-0002-9996-738X;
- Balaram Ghosh - Epigenetic Research Laboratory, Department of Pharmacy, BITS-Pilani, Hyderabad Campus, Shamirpet, Hyderabad 500078, India;https://orcid.org/0000-0002-3425-2439;
- Nilanjan Adhikari - Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, P.O. Box 17020, Kolkata, 700032 West Bengal, India;https://orcid.org/0000-0001-5523-7716
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Biographies
ARTICLE SECTIONS
Nilanjan Adhikari
Nilanjan Adhikari is currently working as an assistant professor in the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. He has completed his B.Pharm. (2007), M.Pharm. (2009) and Ph.D. (2018) degrees from Jadavpur University, Kolkata. He pursued his doctoral and postdoctoral research under the guidance of Prof. Tarun Jha in the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India. His research area includes design, synthesis, and evaluation of anticancer small molecules, especially inhibitors of zinc-dependent metalloenzymes. He is also working on drug design of different bioactive molecules through rigorous computational modeling techniques including quantitative structure–activity relationship (QSAR) analyses. He has published 85 research or review articles in different reputed peer-reviewed journals including eight book chapters.
Tarun Jha
Tarun Jha, a faculty member of the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, has supervised 16 Ph.D. students and guided eight research projects funded by different organizations. He has published more than 150 research articles in different reputed peer-reviewed journals. His research area includes design and synthesis of anticancer small molecules. Prof. Jha is one of the members of the Academic Advisory Committee of the National Board of Accreditation (NBA), New Delhi, India.
Balaram Ghosh
Balaram Ghosh earned B.Pharm. (1998) and M.Pharm. (2000) in Pharmaceutical chemistry from the Department of Pharmaceutical Technology, Jadavpur University, Kolkata. He earned a Ph.D. from the Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan (2009), and worked as a postdoctoral research fellow at Harvard Medical School, Boston, Massachusetts, from 2009 to 2013. Dr. Ghosh joined as an assistant professor in the Department of Pharmacy, BITS-Pilani, Hyderabad campus, in 2013 and has served the institution to the present. The main research interest of his lab includes the development of subtype specific histone deacetylase inhibitors or activators as epigenetic modulators. He has altogether 87 publications, 11 national patents (filed), and 4 international patents (published). He has synthesized BG45, a histone deacetylase 3 inhibitor, which is commercialized by Sigma-Aldrich (Merck).
Acknowledgments
ARTICLE SECTIONS
Nilanjan Adhikari is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India, for providing research associateship (RA) [File No. 09/096(0966)/2019-EMR-I, Dated 28-03-2019]. The research has been supported by the research fund provided by the Council of Scientific and Industrial Research (CSIR-37(1722)/19/EMR-II) to Balaram Ghosh. Tarun Jha is also thankful for the financial support from RUSA 2.0 of UGC, New Delhi, India, to Jadavpur University, Kolkata, India. The authors are thankful to Tarun Kumar Patel and Sravani Pulya of BITS Pilani, Hyderabad Campus, India, as well as Suvankar Banerjee and Sandip Kumar Baidya of Jadavpur University, Kolkata, India, for their assistance. The authors are thankful to the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India, and the Department of Pharmacy, BITS-Pilani, Hyderabad, India, for providing the research facilities.
| Abbreviations Used | |
| AD | Alzheimer’s disease |
| AKAP95 | A-kinase anchor protein 95 |
| AKT | protein kinase B |
| ALI | acute lung injury |
| ALS | amyotrophic lateral sclerosis |
| BMEC | bone marrow endothelial cells |
| BMSC | bone marrow stromal cells |
| CCA | cholangiocarcinoma |
| CDK | cyclin-dependent kinase |
| c-FLIP | cellular FLICK-like inhibitory protein |
| CKD | chronic kidney disease |
| COPD | chronic obstructive pulmonary disease |
| CREB | cAMP-response element binding protein |
| CRPC | castration-resistant prostate cancer |
| CTCL | cutaneous T-cell lymphoma |
| CTGF | connective tissue growth factor |
| CXCR4 | C-X-C chemokine receptor type 4 |
| DAD | deacetylation activating domain |
| DCM | diabetic cardiomyopathy |
| DLBCL | diffused large B-cell lymphoma |
| DNMT1 | DNA methyltransferase 1 |
| DR | death receptor |
| EBD | endothelial barrier dysfunction |
| EGFR | epidermal growth factor receptor |
| ELK | ETS-like protein |
| eNOS | endothelial nitric oxide synthase |
| ERα | estrogen receptor α |
| ERK | extracellular signal-regulated kinase |
| ES | Ewing sarcoma |
| ETS | E26 transformation-specific |
| FLIP | Flice inhibitory protein |
| GFAP | glial fibrillary acidic protein |
| GSIS | glucose stimulated insulin secretion |
| HAT | histone acetyltransferase |
| HCC | hepatocellular carcinoma |
| HDAC | histone deacetylase |
| HD | Huntington’s disease |
| HER2 | human epidermal growth factor 2 |
| HID | histone interacting domain |
| HIF-1α | hypoxia inducible factor-1α |
| HP1 | heterochromatin protein 1 |
| HTLV-1 | human T-cell lymphotropic virus type-1 |
| HSP90 | heat shock protein 90 |
| IAP2 | inhibitor of apoptosis 2 |
| ICAM1 | intracellular adhesion molecule 1 |
| IFN-γ | interferon-γ |
| IL | interleukin |
| IPAH | idiopathic pulmonary arterial hypertension |
| IRF | interferon regulatory factor |
| IRS-1 | insulin receptor substrate-1 |
| JNK | c-Jun N-terminal kinase |
| Keap1 | kelch-like ECH-associated protein 1 |
| LPS | lipopolysaccharide |
| MAPK | mitogen-activated protein kinase |
| MDD | major depressive disorder |
| MCL-1 | myeloid cell leukemia sequence 1 |
| MEF | myocyte enhancer factor |
| MHC | major histocompatibility complex |
| MLC | myosin light chain |
| MM | multiple myeloma |
| MMP | matrix metalloproteinase |
| MR | mineralocorticoid receptor |
| N-CoR | nuclear receptor co-repressor |
| NES | nuclear export signal |
| NF-κB | nuclear factor κB |
| Nrf2 | nuclear transcription of erythroid 2-related factor |
| ONC | optic nerve crush |
| PAI-1 | plasminogen activator inhibitor-1 |
| PARP | poly-ADP ribose polymerase |
| PASMC | pulmonary artery smooth muscle cell |
| PBMC | peripheral blood mononuclear cell |
| PCA | passive cutaneous anaphylaxis |
| PD | Parkinson’s disease |
| PDL-1 | programmed death ligand-1 |
| PEPCK | phosphoenolpyruvate carboxykinase |
| PI3K | phosphoinositide 3-kinase |
| PPAR | peroxisome proliferator-activated receptor |
| PTM | post-translational modification |
| RECK | reversion-inducing cysteine-rich protein with Kazal motifs |
| RAR | retinoic acid receptor |
| RGC | retinal ganglion cell |
| ROS | reactive oxygen species |
| RXR | retinoid X receptor |
| Rpd3 | reduced potassium dependency 3 |
| SCA1 | spinocerebellar ataxia type-1 |
| SCI | spinal cord injury |
| Sir2 | silent information regulator 2 |
| SIRT | sirtuin |
| STAT | signal transducer and activator of transcription |
| SMRT | silencing mediator of retinoic acid thyroid receptor |
| SLE | systemic lupus erythromatous |
| SNP | single nucleotide polymorphism |
| SOD | superoxide dismutase |
| SYK | spleen tyrosine kinase |
| TBP2 | thioredoxin binding protein |
| TGF-β1 | transforming growth factor-β1 |
| TIMP | tissue inhibitor of matrix metalloproteinase |
| TNBC | triple-negative breast cancer |
| TNF-α | tumor necrosis factor-α |
| TpCR | triphasic cutaneous reaction |
| TRAIL | tumor necrosis factor-related apoptosis-inducing ligand |
| VDR | vitamin D receptor |
| VEGF | vascular endothelial growth factor |
| VM | vasculogenic mimicry |
| VSMC | vascular smooth muscle cell |
| XIAP | X-linked inhibitor of apoptosis |
| ZNF-UBP | zinc-finger ubiquitin binding domain |
References
ARTICLE SECTIONS
This article references 308 other publications.
- 1Adhikari, N.; Amin, S. A.; Jha, T. Selective and nonselective HDAC8 inhibitors: A therapeutic patent review. Pharm. Pat. Anal. 2018, 7, 259– 276, DOI: 10.4155/ppa-2018-0019[Crossref], [PubMed], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGgs7s%253D&md5=203ad904b2ba51380c1ccd8f2181e486Selective and nonselective HDAC8 inhibitors: a therapeutic patent reviewAdhikari, Nilanjan; Abdul Amin, Sk; Jha, TarunPharmaceutical Patent Analyst (2018), 7 (6), 259-276CODEN: PPAHCN; ISSN:2046-8954. (Future Science Ltd.)A review. Histone deacetylase 8 (HDAC8) is one of the attractive therapeutic anticancer targets. HDAC8 has been overexpressed in a variety of human cancers. Therefore, HDAC8 inhibitors offer beneficial effects in the treatment of solid and hematol. tumors. Different HDAC inhibitors entered into different phases of clin. studies. However, selectivity towards specific HDAC8 enzyme is still demanding. In this patent review, a no. of patented selective and nonselective HDAC8 inhibitors along with their implication as anticancer agents have been discussed in details. Mols. should possess modified fish-like structural arrangement to impart potency and selectivity towards HDAC8. This comprehensive patent anal. will surely provide newer aspects of designing selective HDAC8 inhibitors targeted to anticancer therapy in future.
- 2Biswas, S.; Rao, C. M. Epigenetics in cancer: fundamentals and beyond. Pharmacol. Ther. 2017, 173, 118– 134, DOI: 10.1016/j.pharmthera.2017.02.011[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXislOru7o%253D&md5=1173d02b0cc70a467944d59d2d2a35fcEpigenetics in cancer: Fundamentals and BeyondBiswas, Subhankar; Rao, C. MallikarjunaPharmacology & Therapeutics (2017), 173 (), 118-134CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Activation of oncogenes or the deactivation of tumor suppressor genes has long been established as the fundamental mechanism leading towards carcinogenesis. Although this age old axiom is vastly accurate, thorough study over the last 15 years has given us unprecedented information on the involvement of epigenetic in cancer. Various biochem. pathways that are essential towards tumorigenesis are regulated by the epigenetic phenomenons like remodeling of nucleosome by histone modifications, DNA methylation and miRNA mediated targeting of various genes. Moreover the presence of mutations in the genes controlling the epigenetic players has further strengthened the assocn. of epigenetics in cancer. This merger has opened up newer avenues for targeted anti-cancer drug therapy with numerous pharmaceutical industries focusing on expanding their research and development pipeline with epigenetic drugs. The information provided here elaborates the elementary phenomena of the various epigenetic regulators and discusses their alteration assocd. with the development of cancer. We also highlight the recent developments in epigenetic drugs combining preclin. and clin. data to signify this evolving field in cancer research.
- 3Amin, S. A.; Adhikari, N.; Kotagiri, S.; Jha, T.; Ghosh, B. Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides. Eur. J. Med. Chem. 2019, 166, 369– 380, DOI: 10.1016/j.ejmech.2019.01.077[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivFygtLo%253D&md5=f4ca2691087eb3ee67a53e1feda65568Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamidesAmin, Sk. Abdul; Adhikari, Nilanjan; Kotagiri, Sonali; Jha, Tarun; Ghosh, BalaramEuropean Journal of Medicinal Chemistry (2019), 166 (), 369-380CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cAMP -response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a neg. regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biol. and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.
- 4Amin, S. A.; Adhikari, N.; Ghosh, B.; Jha, T. Histone Deacetylase 3 and Its inhibitors. In Advances in Medicine and Biology; Berhardt, L. V., Ed.; Nova Science Publishers: New York, 2019; Vol. 145, Chapter 4, pp 131– 202.
- 5Sarkar, R.; Banerjee, S.; Amin, S. A.; Adhikari, N.; Jha, T. Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review. Eur. J. Med. Chem. 2020, 192, 112171, DOI: 10.1016/j.ejmech.2020.112171[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvVeisr0%253D&md5=d9911556755793d92c3e073b89b9b00eHistone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A reviewSarkar, Rajat; Banerjee, Suvankar; Amin, Sk Abdul; Adhikari, Nilanjan; Jha, TarunEuropean Journal of Medicinal Chemistry (2020), 192 (), 112171CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Among different Histone deacetylases (HDACs), histone deacetylase 3 (HDAC3) is an epigenetic drug target which is currently marked as a potential therapeutic strategy to combat various cancers. HDAC3 inhibitors are effective for the treatment of cancers, different neurodegenerative disorders, diabetes mellitus, cardiac diseases, HIV, inflammatory diseases, rheumatoid arthritis (RA), etc. Inhibition of HDAC3 metalloenzyme is a dynamic approach for drug design and discovery. This approach has gained considerable interest in recent years. The development of an effective therapeutic agent against HDAC3 is still challenging. A lot of work is still in demand. This current communication is a part of our extended work on HDAC3 inhibitors to achieve deep insight of knowledge about the structural information of HDAC3 inhibitors. This article is unique in terms of detailed structure-activity relationships (SARs) anal. This may help to find out some important clues to design better active HDAC3 inhibitors in the future.
- 6Banerjee, S.; Adhikari, N.; Amin, S. A.; Jha, T. Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview. Eur. J. Med. Chem. 2019, 164, 214– 240, DOI: 10.1016/j.ejmech.2018.12.039[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltF2q&md5=cf4ca3ae21d10662da0ce32f0c336b72Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overviewBanerjee, Suvankar; Adhikari, Nilanjan; Amin, Sk Abdul; Jha, TarunEuropean Journal of Medicinal Chemistry (2019), 164 (), 214-240CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiol. and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiol. conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymic activity.
- 7Chakrabarti, A.; Oehme, I.; Witt, O.; Oliveira, G.; Sippl, W.; Romier, C.; Pierce, R. J.; Jung, M. HDAC8: A multifaceted target for therapeutic interventions. Trends Pharmacol. Sci. 2015, 36, 481– 492, DOI: 10.1016/j.tips.2015.04.013[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotlGqsL4%253D&md5=c99b5c390930dc17398d15f20127758bHDAC8: a multifaceted target for therapeutic interventionsChakrabarti, Alokta; Oehme, Ina; Witt, Olaf; Oliveira, Guilherme; Sippl, Wolfgang; Romier, Christophe; Pierce, Raymond J.; Jung, ManfredTrends in Pharmacological Sciences (2015), 36 (7), 481-492CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors crit. to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.
- 8Amin, S. A.; Adhikari, N.; Jha, T. Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery. Future Med. Chem. 2017, 9, 2211– 2237, DOI: 10.4155/fmc-2017-0130[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3ls1eitg%253D%253D&md5=f0dced85072243a221ab3d666576f424Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discoveryAmin Sk Abdul; Adhikari Nilanjan; Jha TarunFuture medicinal chemistry (2017), 9 (18), 2211-2237 ISSN:.The pan-histone deacetylase (HDAC) inhibitors comprise a fish-like structural orientation where hydrophobic aryl- and zinc-binding groups act as head and tail, respectively of a fish. The linker moiety correlates the body of the fish linking head and tail groups. Despite these pan-HDAC inhibitors, selective HDAC-8 inhibitors are still in demand as a safe remedy. HDAC-8 is involved in invasion and metastasis in cancer. This review deals with the rationale behind HDAC-8 inhibitory activity and selectivity along with detailed structure-activity relationships of diverse hydroxamate-based HDAC-8 inhibitors. HDAC-8 inhibitory potency may be increased by modifying the fish-like pharmacophoric features of such type of pan-HDAC inhibitors. This review may provide a preliminary basis to design and optimize new lead molecules with higher HDAC-8 inhibitory activity. This work may surely enlighten in providing useful information in the field of target-specific anticancer therapy.
- 9Gregoretti, I. V.; Lee, Y. M.; Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 2004, 338, 17– 31, DOI: 10.1016/j.jmb.2004.02.006[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisFyksro%253D&md5=1748e3b88d8f3b774db50eb19799f63cMolecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic AnalysisGregoretti, Ivan V.; Lee, Yun-Mi; Goodson, Holly V.Journal of Molecular Biology (2004), 338 (1), 17-31CODEN: JMOBAK; ISSN:0022-2836. (Elsevier)Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic agents against cancer and a variety of other diseases. Thus far, 11 members of the HDAC family have been identified in humans, but few have been characterized in detail. To better define the biol. function of these proteins, make maximal use of studies performed in other systems, and assist in drug development efforts, we have performed a phylogenetic anal. of all HDAC-related proteins in all fully sequenced free-living organisms. Previous analyses have divided non-sirtuin HDACs into two groups, classes 1 and 2. We find that HDACs can be divided into three equally distinct groups: class 1, class 2, and a third class consisting of proteins related to the recently identified human HDAC11 gene. We term this novel group "class 4" to distinguish it from the unrelated "class 3" sirtuin deacetylases. Anal. of gene duplication events indicates that the common ancestor of metazoan organisms contained two class 1, two class 2, and a single class 4 HDAC. Examn. of HDAC characteristics in light of these evolutionary relationships leads to functional predictions, among them that self-assocn. is common among HDAC proteins. All three HDAC classes (including class 4) exist in eubacteria. Phylogenetic anal. of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against non-histone substrates.
- 10Fu, W.; Wu, K.; Duan, J. Sequence and expression analysis of histone deacetylases in rice. Biochem. Biophys. Res. Commun. 2007, 356, 843– 850, DOI: 10.1016/j.bbrc.2007.03.010[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvFOmsbY%253D&md5=38a512409528357bd76945a28b96db3bSequence and expression analysis of histone deacetylases in riceFu, Wenqun; Wu, Keqiang; Duan, JunBiochemical and Biophysical Research Communications (2007), 356 (4), 843-850CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)Histone acetylation levels are detd. by the action of histone acetyltransferases and histone deacetylases (HDACs). Sequence similarity and profile searching tools were used to analyze the genome sequence of rice (Oryzae sativa) for genes encoding HDAC proteins. The rice RPD3/HDA1-family HDAC proteins can be divided into four classes based on sequence similarity and phylogenetic anal. of sequences obtained from the rice genome. The spatial expression pattern of rice HDACs genes indicated that some HDAC genes have different expression profiles. Furthermore, our anal. indicated that expression of HDA705, HDT701, and HDT702 could be affected by salicylic acid, jasmonic acid or abscisic acid. Expression of HDA714, SRT702, and SRT701 could be modulated by abiotic stresses, such as cold, mannitol and salt. These results indicate that different HDAC genes have distinct expression patterns and members of rice HDAC families may be involved in plant response to environmental stresses.
- 11Mano, T.; Suzuki, T.; Tsuji, S.; Iwata, A. Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates. PLoS One 2014, 9, e111277 DOI: 10.1371/journal.pone.0111277[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOksLfN&md5=7340313f14bf09977cbec1d5374fdbe5Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregatesMano, Tatsuo; Suzuki, Takayoshi; Tsuji, Shoji; Iwata, AtsushiPLoS One (2014), 9 (11), e111277/1-e111277/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington's disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addn. to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amt. of Htt aggregates by increasing the amt. of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation.
- 12Verdin, E.; Dequiedt, F.; Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 2003, 19, 286– 293, DOI: 10.1016/S0168-9525(03)00073-8[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtFeqt7o%253D&md5=0d9eca937cd5bd87e1f0640ab6223de4Class II histone deacetylases: versatile regulatorsVerdin, Eric; Dequiedt, Franck; Kasler, Herbert G.Trends in Genetics (2003), 19 (5), 286-293CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)A review. Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of Lys residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into 3 classes based on their similarity to known yeast factors: class I HDACs are similar to yeast transcriptional repressor yRPD3, class II HDACs to yHDA1, and class III HDACs to ySIR2. Here, the focus is on the biol. of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. The authors discuss their emerging biol. functions and the mol. mechanisms by which they are regulated.
- 13Lahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.; Jones, P.; Neddermann, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.; De Francesco, R.; Steinkühler, C.; Gallinari, P. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17335– 17340, DOI: 10.1073/pnas.0706487104[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ymtrjO&md5=a8345ac68fbddc344e9e0737472e2863Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylasesLahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.; Jones, P.; Neddermann, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.; De Francesco, R.; Steinkuehler, C.; Gallinari, P.Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (44), 17335-17340CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on std. substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymic assay, suggesting that the obsd. activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on std. substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nε2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this "gain of function phenotype" could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
- 14Zhang, Y.; Li, N.; Caron, C.; Matthias, G.; Hess, D.; Khochbin, S.; Matthias, P. HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 2003, 22, 1168– 1179, DOI: 10.1093/emboj/cdg115[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXit1yls7c%253D&md5=0d2b6dd552163866b85f14471ac600f7HDAC-6 interacts with and deacetylates tubulin and microtubules in vivoZhang, Yu; Li, Na; Caron, Cecile; Matthias, Gabriele; Hess, Daniel; Khochbin, Saadi; Matthias, PatrickEMBO Journal (2003), 22 (5), 1168-1179CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Microtubules are cylindrical cytoskeletal structures found in almost all eukaryotic cell types which are involved in a great variety of cellular processes. Reversible acetylation on the ε-amino group of α-tubulin Lys40 marks stabilized microtubule structures and may contribute to regulating microtubule dynamics. Yet, the enzymes catalyzing this acetylation/deacetylation have remained unidentified until recently. Here we report that β-tubulin interacts with histone deacetylase-6 (HDAC-6) in a yeast two-hybrid assay and in vitro. We find that HDAC-6 is a micro tubule-assocd. protein capable of deacetylating α-tubulin in vivo and in vitro. HDAC-6's microtubule binding and deacetylation functions both depend on the hdac domains. Overexpression of HDAC-6 in mammalian cells leads to tubulin hypoacetylation. In contrast, inhibition of HDAC-6 function by two independent mechanisms-pharmacol. (HDAC inhibitors) or genetic (targeted inactivation of HDAC-6 in embryonic stem cells)-leads to hyperacetylation of tubulin and microtubules. Taken together, our data provide evidence that HDAC-6 might act as a dual deacetylase for tubulin and histones, and suggest the possibility that acetylated non-histone proteins might represent novel targets for pharmacol. therapy by HDAC inhibitors.
- 15Gao, L.; Cueto, M. A.; Asselbergs, F.; Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 2002, 277, 25748– 25755, DOI: 10.1074/jbc.M111871200[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlsVWht7g%253D&md5=9d22c3b434691e5bce5e13db8b500eddCloning and functional characterization of HDAC11, a novel member of the human histone deacetylase familyGao, Lin; Cueto, Maria A.; Asselbergs, Fred; Atadja, PeterJournal of Biological Chemistry (2002), 277 (28), 25748-25755CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The authors have cloned and characterized a human cDNA that belongs to the histone deacetylase family, which the authors designate as HDAC11. The predicted HDAC11 amino acid sequence reveals an open reading frame of 347 residues with a corresponding mol. mass of 39 kDa. Sequence analyses of the putative HDAC11 protein indicate that it contains conserved residues in the catalytic core regions shared by both class I and II mammalian HDAC enzymes. Putative orthologs of HDAC11 exist in primate, mouse, Drosophila, and plant. Epitope-tagged HDAC11 protein expressed in mammalian cells displays histone deacetylase activity in vitro. Furthermore, HDAC11's enzymic activity is inhibited by trapoxin, a known histone deacetylase inhibitor. Multiple tissue Northern blot and real-time PCR expts. show that the high expression level of HDAC11 transcripts is limited to kidney, heart, brain, skeletal muscle, and testis. Epitope-tagged HDAC11 protein localizes predominantly to the cell nucleus. Co-immunopptn. expts. indicate that HDAC11 may be present in protein complexes that also contain HDAC6. These results indicate that HDAC11 is a novel and unique member of the histone deacetylase family and it may have distinct physiol. roles from those of the known HDACs.
- 16Mrakovcic, M.; Kleinheinz, J.; Fröhlich, L. F. p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Int. J. Mol. Sci. 2019, 20, 2415, DOI: 10.3390/ijms20102415[Crossref], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosVGmsg%253D%253D&md5=d74b939314d54d581024c3ef97664733In p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell deathMrakovcic, Maria; Kleinheinz, Johannes; Froehlich, Leopold F.International Journal of Molecular Sciences (2019), 20 (10), 2415/1-2415/32CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of both histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy, which are either mutually exclusive or activated in combination. Here, we compile known mol. signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that det. the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to det. the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment.
- 17Manal, M.; Chandrasekar, M. J.; Gomathi Priya, J.; Nanjan, M. J. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg. Chem. 2016, 67, 18– 42, DOI: 10.1016/j.bioorg.2016.05.005[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xoslaltbc%253D&md5=82e5562d9b74dfef2d6077bbceccd505Inhibitors of histone deacetylase as antitumor agents: A critical reviewManal, Mohammed; Chandrasekar, M. J. N.; Gomathi Priya, Jeyapal; Nanjan, M. J.Bioorganic Chemistry (2016), 67 (), 18-42CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A review. Histone deacetylase (E.C. 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and nonhistone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clin. trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chem. of the mols. of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer.
- 18Xu, W. S.; Parmigiani, R. B.; Marks, P. A. Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 2007, 26, 5541– 5552, DOI: 10.1038/sj.onc.1210620[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXovFersrY%253D&md5=227a7c5d26028e99d412441596ba02aeHistone deacetylase inhibitors: molecular mechanisms of actionXu, W. S.; Parmigiani, R. B.; Marks, P. A.Oncogene (2007), 26 (37), 5541-5552CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered targeted' anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homol. to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clin. trials, vorinostat has activity against hematol. and solid cancers at doses well tolerated by patients. In addn. to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called 'lysine deacetylases.'. HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of mol. alterations present in different cancer cells.
- 19Richon, V. M.; Sandhoff, T. W.; Rifkind, R. A.; Marks, P. A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 10014– 10019, DOI: 10.1073/pnas.180316197[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtlehsL4%253D&md5=7ada3abdf0a2109b73efa2770d5db6cbHistone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylationRichon, Victoria M.; Sandhoff, Todd W.; Rifkind, Richard A.; Marks, Paul A.Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (18), 10014-10019CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the amino-terminal lysine residues of core nucleosomal histones. This activity is assocd. generally with transcriptional repression. We have reported previously that inhibition of HDAC activity by hydroxamic acid-based hybrid polar compds., such as suberoylanilide hydroxamic acid (SAHA), induces differentiation and/or apoptosis of transformed cells in vitro and inhibits tumor growth in vivo. SAHA is a potentially new therapeutic approach to cancer treatment and is in Phase I clin. trials. In several tumor cell lines examd., HDAC inhibitors alter the expression of less than 1% of expressed genes, including the cell cycle kinase inhibitor p21WAF1. In T24 bladder carcinoma cells, SAHA induces up to a 9-fold increase in p21WAF1 mRNA and protein, which is, at least in part, because of an increase in the rate of transcription of the gene. SAHA causes an accumulation of acetylated histones H3 and H4 in total cellular chromatin by 2 h, which is maintained through 24 h of culture. An increase in the accumulation of acetylated H3 and H4 was detected throughout the p21WAF1 promoter and the structural gene after culture with SAHA. The level of histone acetylation did not change in chromatin assocd. with the actin and p27 genes, and their mRNA expression was not altered during culture of T24 cells with SAHA. Thus, the present findings indicate that the induction of p21WAF1 by SAHA is regulated, at least in part, by the degree of acetylation of the gene-assocd. histones and that this induced increase in acetylation is gene selective.
- 20Nawrocki, S. T.; Carew, J. S.; Douglas, L.; Cleveland, J. L.; Humphreys, R.; Houghton, J. A. Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21 Cip1-dependent decrease in survivin levels. Cancer Res. 2007, 67, 6987– 6994, DOI: 10.1158/0008-5472.CAN-07-0812[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnslOitL8%253D&md5=9409f3e41a5ddfa903b76d2a6dfa8123Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin LevelsNawrocki, Steffan T.; Carew, Jennifer S.; Douglas, Leslie; Cleveland, John L.; Humphreys, Robin; Houghton, Janet A.Cancer Research (2007), 67 (14), 6987-6994CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was crit. for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21+/+ cells but not in the HCT116 p21-/- cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
- 21Wang, H.; Zhou, W.; Zheng, Z.; Zhang, P.; Tu, B.; He, Q.; Zhu, W. G. The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair 2012, 11, 146– 156, DOI: 10.1016/j.dnarep.2011.10.014[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVCksw%253D%253D&md5=eefbeedd5c1475560e83c20359b45cc9The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damageWang, Haiying; Zhou, Wen; Zheng, Zhixing; Zhang, Ping; Tu, Bo; He, Qihua; Zhu, Wei-GuoDNA Repair (2012), 11 (2), 146-156CODEN: DRNEAR; ISSN:1568-7864. (Elsevier B.V.)Histone deacetylase (HDAC) inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin. As a potent HDAC inhibitor, depsipeptide not only modulates histone deacetylation but also activates non-histone protein p53 to inhibit cancer cell growth. However, the mechanism of depsipeptide-induced p53 transactivity remains unknown. Here, we show that depsipeptide causes DNA damage through induction of reactive oxygen species (ROS) generation, as demonstrated by a comet assay and by detection of the phosphorylation of H2AX. Depsipeptide induced oxidative stress was confirmed to relate to a disturbance in redn.-oxidn. (redox) reactions through inhibition of the transactivation of thioredoxin reductase (TrxR) in human cancer cells. Upon treatment with depsipeptide, p53 phosphorylation at threonine 18 (Thr18) was specifically induced. Furthermore, we also demonstrated that phosphorylation of p53 at Thr18 is required for p53 acetylation at lysine 373/382 and for p21 expression in response to depsipeptide treatment. Our results demonstrate that depsipeptide plays an anti-neoplastic role by generating ROS to elicit p53/p21 pathway activation.
- 22Schrump, D. S. Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin. Cancer Res. 2009, 15, 3947– 3957, DOI: 10.1158/1078-0432.CCR-08-2787[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlOis74%253D&md5=5c00e794043ab54dc9116537b31afb9cCytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical ImplicationsSchrump, David S.Clinical Cancer Research (2009), 15 (12), 3947-3957CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacol. agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clin. implications of HDAC inhibition as a strategy for cancer therapy.
- 23Li, H.; Wu, X. Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. Biochem. Biophys. Res. Commun. 2004, 324, 860– 867, DOI: 10.1016/j.bbrc.2004.09.130[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotlCmtrk%253D&md5=085568cab56226e68e0cb41dcb87bea0Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cellsLi, Hui; Wu, XinxingBiochemical and Biophysical Research Communications (2004), 324 (2), 860-867CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)Histone deacetylase (HDAC) inhibitors have shown promise in clin. cancer therapy and to consistently induce p21WAF1/CIP1 expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21WAF1/CIP1 promoter region. However, the exact mechanism by which HDAC inhibitors induce p21WAF1/CIP1 remains unclear. In this study, we obsd. that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21WAF1/CIP1 expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21WAF1/CIP1 in these cancer cells. These data suggest that c-myc may play a crit. role in repression of p21WAF1/CIP1 expression in HeLa cells. More importantly, using chromatin immunopptn. assay, we obsd. for the first time that c-myc bound to the endogenous p21WAF1/CIP1 promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21WAF1/CIP1 promoter contributes, at least partially, to transcriptional activation of the p21WAF1/CIP1 in HeLa cells.
- 24Robbins, A. R.; Jablonski, S. A.; Yen, T. J.; Yoda, K.; Robey, R.; Bates, S. E.; Sackett, D. L. Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle 2005, 4, 717– 726, DOI: 10.4161/cc.4.5.1690[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVOnsrY%253D&md5=f6190ef862d5b673c3858a9e59316257Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatinRobbins, April R.; Jablonski, Sandra A.; Yen, Tim J.; Yoda, Kinya; Robey, Rob; Bates, Susan E.; Sackett, Dan L.Cell Cycle (2005), 4 (5), 717-726CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)The kinetochore, a multi-protein complex assembled on centromeric chromatin in mitosis, is essential for sister chromosome segregation. We show here that inhibition of histone deacetylation blocks mitotic progression at prometaphase in two human tumor cell lines by interfering with kinetochore assembly. Decreased amts. of hBUB1, CENP-F and the motor protein CENP-E were present on kinetochores of treated cells. These kinetochores failed to nucleate and inefficiently captured microtubules, resulting in activation of the mitotic checkpoint. Addn. of histone deacetylase inhibitors prior to the end of S-phase resulted in decreased HP1-β on pericentromeric heterochromatin in S-phase and G2, decreased pericentromeric targeting of Aurora B kinase, resulting in decreased premitotic phosphorylation of pericentromeric histone H3(S10) in G2, followed by assembly of deficient kinetochores in M-phase. HP1-β, Aurora B and the affected kinetochore proteins all were present at normal levels in treated cells; thus, effects of the inhibitors on mitotic progression do not seem to reflect changes in gene expression. In vitro kinase activity of Aurora B isolated from treated cells was unaffected. We propose that the increased presence in pericentromeric heterochromatin of histone H3 acetylated at K9 is responsible for the mitotic defects resulting from inhibition of histone deacetylation.
- 25Magnaghi-Jaulin, L.; Eot-Houllier, G.; Fulcrand, G.; Jaulin, C. Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint. Cancer Res. 2007, 67, 6360– 6367, DOI: 10.1158/0008-5472.CAN-06-3012[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnsVyqtLs%253D&md5=b5cabbd79fdcd6cfb404175541cbb3aeHistone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpointMagnaghi-Jaulin, Laura; Eot-Houllier, Gregory; Fulcrand, Geraldine; Jaulin, ChristianCancer Research (2007), 67 (13), 6360-6367CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Histone deacetylase inhibitors (HDACI) are /powerful antiproliferative drugs, and are currently undergoing clin. trials as antitumor agents. It would be valuable for both cancer therapy and our knowledge of basic cellular processes to understand the mechanisms by which HDACIs block cell proliferation. Most current models postulate that HDACIs allow the reexpression of tumor suppressor genes silenced in cancer cells. However, other mechanisms, distinct from transcription regulation, may participate in HDACI antiproliferative properties. We report that HDACI treatment induces premature sister chromatid sepn. in cells in which the mitotic spindle assembly checkpoint (SAC) has already been activated. This effect was transcription-independent. In addn., HDACI-treated mitotic cells displayed SAC inactivation characteristics, including anaphase-promoting complex/cyclosome target degrdn., cyclin-dependent kinase 1 inactivation, histone H3 dephosphorylation, and loss of the SAC component MAD2 from the kinetochore. Thus, HDAC inhibition renders the SAC ineffective. Our findings help elucidate the mol. mechanisms of proliferative cell death induced by HDACI treatment and may allow new HDACI-based preclin. and clin. trial protocols to be redesigned so as to target mitosis.
- 26Dowling, M.; Voong, K. R.; Kim, M.; Keutmann, M. K.; Harris, E.; Kao, G. D. Mitotic spindle checkpoint inactivation by trichostatin a defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents. Cancer Biol. Ther. 2005, 4, 205, DOI: 10.4161/cbt.4.2.1441
- 27Liu, L. T.; Chang, H. C.; Chiang, L. C.; Hung, W. C. Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res. 2003, 63, 3069– 3072[PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1eitLk%253D&md5=92b3c13b7eaa1f61d53f5345e2f1f7daHistone Deacetylase Inhibitor Up-Regulates RECK to Inhibit MMP-2 Activation and Cancer Cell InvasionLiu, Li-Teh; Chang, Hui-Chiu; Chiang, Lien-Chai; Hung, Wen-ChunCancer Research (2003), 63 (12), 3069-3072CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Histone deacetylase (HDAC) inhibitors are known to exert antimetastatic and antiangiogenic activity in vitro and in vivo. RECK is a membrane-anchored glycoprotein that neg. regulates matrix metalloproteinases (MMPs) and inhibits tumor metastasis and angiogenesis. In this study, we test the possibility that HDAC inhibitor may increase RECK expression to inhibit MMP activation and cancer cell invasion. Our results showed that trichostatin A (TSA) up-regulated RECK via transcriptional activation in CL-1 human lung cancer cells. Flow cytometric anal. demonstrated that RECK protein on cell surface was increased after treatment of TSA. Moreover, up-regulation of RECK expression by TSA attenuated MMP-2 activity. To explore whether HDAC inhibitor-induced inhibition of MMP-2 activation is indeed mediated via RECK, we used small interference RNA (siRNA) to block RECK expression and found that inhibition of RECK by siRNA abolished the inhibitory effect of TSA on MMP-2 activation. In addn., TSA suppressed the invasive ability of CL-1 cells. Taken together, this study reveals a novel mechanism by which HDAC inhibitors suppress tumor invasion and provides a new strategy for cancer therapy.
- 28Estella, C.; Herrer, I.; Atkinson, S. P.; Quiñonero, A.; Martínez, S.; Pellicer, A.; Simon, C. Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion. PLoS One 2012, 7, e30508 DOI: 10.1371/journal.pone.0030508[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitlaqsLo%253D&md5=63831500a8b1697799d6597b4bd40a0aInhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasionEstella, Carlos; Herrer, Isabel; Atkinson, Stuart P.; Quinonero, Alicia; Martinez, Sebastian; Pellicer, Antonio; Simon, CarlosPLoS One (2012), 7 (1), e30508CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Invasion of the trophoblast into the maternal decidua is regulated by both the trophectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins, and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpack condensed chromatin activating gene expression. In this study, we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3; decreased MMP-2, MMP-9 and uPA and had an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated cells. In addn., in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is assocd. with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.
- 29Tran, A. D. A.; Marmo, T. P.; Salam, A. A.; Che, S.; Finkelstein, E.; Kabarriti, R.; Xenias, H. S.; Mazitschek, R.; Hubbert, C.; Kawaguchi, Y.; Sheetz, M. P.; Yao, T. P.; Bulinski, J. C. HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J. Cell Sci. 2007, 120, 1469– 1479, DOI: 10.1242/jcs.03431[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsFSjtbs%253D&md5=6e25ead47afba657cf58bf4287df25fbHDAC6 deacetylation of tubulin modulates dynamics of cellular adhesionsTran, Andy Dong-Anh; Marmo, Timothy P.; Salam, Ambar A.; Che, Sally; Finkelstein, Erik; Kabarriti, Rafi; Xenias, Harry S.; Mazitschek, Ralph; Hubbert, Charlotte; Kawaguchi, Yoshiharu; Sheetz, Michael P.; Yao, Tso-Pang; Bulinski, J. ChloeJournal of Cell Science (2007), 120 (8), 1469-1479CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)Genetic or pharmacol. alteration of the activity of histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of α-tubulin, and not other HDAC6 substrates, yielded a motility redn. equiv. to agents that block all NAD-independent HDACs. Accordingly, the authors investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited cells. Testing the hypothesis that motility is reduced because cellular adhesion is altered, it was found that inhibiting HDAC6 activity toward tubulin rapidly increased the total adhesion area. Next, the authors investigated the mechanism of the adhesion area increase. Formation of adhesions proceeded normally and cell spreading was more rapid in the absence of active HDAC6; however, photobleaching assays and adhesion breakdown showed that adhesion turnover was slower. To test the role of hyperacetylated tubulin in altering adhesion turnover, the authors measured microtubule dynamics in HDAC6-inhibited cells because dynamic microtubules are required to target adhesions for turnover. HDAC6 inhibition yielded a decrease in microtubule dynamics that was sufficient to decrease focal adhesion turnover. Thus, the results suggest a scenario in which the decreased dynamics of hyperacetylated microtubules in HDAC6-inhibited cells compromises their capacity to mediate the focal adhesion dynamics required for rapid cell migration.
- 30Terui, T.; Murakami, K.; Takimoto, R.; Takahashi, M.; Takada, K.; Murakami, T.; Minami, S.; Matsunaga, T.; Takayama, T.; Kato, J.; Niitsu, Y. Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. Cancer Res. 2003, 63, 8948– 8954[PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVSqtbnM&md5=32a8a2d566f752ac86b10c469ee11e5eInduction of PIG3 and NOXA through Acetylation of p53 at 320 and 373 Lysine Residues as a Mechanism for Apoptotic Cell Death by Histone Deacetylase InhibitorsTerui, Takeshi; Murakami, Ken; Takimoto, Rishu; Takahashi, Minoru; Takada, Koichi; Murakami, Tsuzuku; Minami, Shinya; Matsunaga, Takuya; Takayama, Tetsuji; Kato, Junji; Niitsu, YoshiroCancer Research (2003), 63 (24), 8948-8954CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 mol. at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.
- 31Inoue, S.; Riley, J.; Gant, T. W.; Dyer, M. J.; Cohen, G. M. Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by bim and noxa. Leukemia 2007, 21, 1773– 1782, DOI: 10.1038/sj.leu.2404760[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnvVeltbk%253D&md5=722720f03d80c397ac194e922033ae6fApoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and NoxaInoue, S.; Riley, J.; Gant, T. W.; Dyer, M. J. S.; Cohen, G. M.Leukemia (2007), 21 (8), 1773-1782CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Several histone deacetylase inhibitors (HDACi), which have recently entered early clin. trials, exert their anticancer activity in part through the induction of apoptosis although the precise mechanism of this induction is not known. Induction of apoptosis by structurally diverse HDACi in primary cells from patients with chronic lymphocytic leukemia (CLL) and different leukemic cell lines was mediated by the Bcl-2 regulated intrinsic pathway and demonstrated a requirement for de novo protein synthesis. A marked time-dependent induction of the pro-apoptotic BH3-only proteins, Bim, Noxa and Bmf was obsd., which preceded the induction of apoptosis. A key role for both Bim and Noxa was proposed in HDACi-mediated apoptosis based on our findings that siRNA for Bim and Noxa but not Bmf largely prevented the HDACi-induced loss in mitochondrial membrane potential, caspase processing and phosphatidylserine externalization. Noxa, induced by HDACi, in CLL cells and tumor cell lines, bound extensively to Mcl-1, a major anti-apoptotic Bcl-2 family member present in CLL cells. Our data strongly suggests that HDACi induce apoptosis primarily through inactivation of anti-apoptotic Bcl-2 family members by increases in Bim and Noxa and highlights these increases as a potential clin. target for CLL/lymphoma therapy.
- 32Zhang, X. D.; Gillespie, S. K.; Borrow, J. M.; Hersey, P. The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Biochem. Pharmacol. 2003, 66, 1537– 1545, DOI: 10.1016/S0006-2952(03)00509-4[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVeqs7s%253D&md5=095588ae46c4ab5fe4f39e583b658955The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosisZhang, Xu Dong; Gillespie, Susan K.; Borrow, Jodie M.; Hersey, PeterBiochemical Pharmacology (2003), 66 (8), 1537-1545CODEN: BCPCA6; ISSN:0006-2952. (Elsevier Science B.V.)A review. TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-XL and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.
- 33Bolden, J. E.; Shi, W.; Jankowski, K.; Kan, C. Y.; Cluse, L.; Martin, B. P.; MacKenzie, K. L.; Smyth, G. K.; Johnstone, R. W. HDAC inhibitors induce tumor-cell selective pro-apoptotic transcriptional responses. Cell Death Dis. 2013, 4, e519 DOI: 10.1038/cddis.2013.9[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyksbbJ&md5=68ece9fa3ee1f2a3e7e4ef75229da5deHDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responsesBolden, J. E.; Shi, W.; Jankowski, K.; Kan, C.-Y.; Cluse, L.; Martin, B. P.; MacKenzie, K. L.; Smyth, G. K.; Johnstone, R. W.Cell Death & Disease (2013), 4 (Feb.), e519CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compds. that target the epigenome for the treatment of cancer. This notion is supported by biochem. studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through assocn. with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biol. and mol. responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontol. and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells while leaving normal cells relatively unharmed is fundamental to their successful clin. application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific mols. and pathways in the tumor-selective cytotoxic activity of these compds.
- 34Zhang, Y.; Adachi, M.; Kawamura, R.; Imai, K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 2006, 13, 129– 140, DOI: 10.1038/sj.cdd.4401686[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yktbrN&md5=54bc6d7d5842e9c4649ebd3d5b7b3e4aBmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosisZhang, Y.; Adachi, M.; Kawamura, R.; Imai, K.Cell Death and Differentiation (2006), 13 (1), 129-140CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)Histone deacetylase (HDAC) inhibitors modify transcription of selected genes and eventually induce apoptosis. However, mol. mechanisms for their proapoptotic activity remain unclear. We here demonstrate that HDAC inhibitors FK228 and CBHA preferentially upregulated the BH3-only protein Bmf in a broad range of cancer cells. In contrast, HDAC1 overexpression distinctly reduced Bmf expression. FK228 induced histones H3 and H4 acetylation at Bmf promoter region, but not at its 3' region, suggesting that histone hyperacetylation causes Bmf transcriptional activation. Knockdown of Bmf transcripts rescued cells from FK228 or CBHA-induced cell death, disruption of mitochondrial membrane potential (ΔΨm) and DNA fragmentation. Taken together, FK228 and CBHA activate Bmf transcription by histone hyperacetylation at its promoter region, and inhibition of this action decreased their proapoptotic activity, thereby highlighting a central role of Bmf in HDAC inhibitor-mediated apoptosis.
- 35Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discovery 2006, 5, 769– 784, DOI: 10.1038/nrd2133[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVCltrY%253D&md5=91e55ee942fda3e4e2055ddf299fc866Anticancer activities of histone deacetylase inhibitorsBolden, Jessica E.; Peart, Melissa J.; Johnstone, Ricky W.Nature Reviews Drug Discovery (2006), 5 (9), 769-784CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addn., the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes assocd. with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclin. studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the mol. events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
- 36Tang, S.; Cheng, B.; Zhe, N.; Ma, D.; Xu, J.; Li, X.; Guo, Y.; Wu, W.; Wang, J. Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway. Anti-Cancer Drugs 2018, 29, 61– 74, DOI: 10.1097/CAD.0000000000000568[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFOitbzN&md5=ea90a24c0f18f4018affc32f27a83fd4Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathwayTang, Sishi; Cheng, Bingqing; Zhe, Nana; Ma, Dan; Xu, Jibing; Li, Xinyao; Guo, Yongling; Wu, Weibing; Wang, JishiAnti-Cancer Drugs (2018), 29 (1), 61-74CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)Multiple myeloma (MM) is a hematol. malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of mol. targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, esp. the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clin. use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematol. malignancies.
- 37Al-Yacoub, N.; Fecker, L. F.; Möbs, M.; Plötz, M.; Braun, F. K.; Sterry, W.; Eberle, J. Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J. Invest. Dermatol. 2012, 132, 2263– 2274, DOI: 10.1038/jid.2012.125[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlGqtbk%253D&md5=585527a348f26be6561e5b9968692222Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL SignalingAl-Yacoub, Nadya; Fecker, Lothar F.; Moebs, Markus; Ploetz, Michael; Braun, Frank K.; Sterry, Wolfram; Eberle, JuergenJournal of Investigative Dermatology (2012), 132 (9), 2263-2274CODEN: JIDEAE; ISSN:0022-202X. (Nature Publishing Group)Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, whereas cytotoxicity was less pronounced. Both extrinsic and intrinsic apoptosis pathways were activated, as seen by processing of initiator caspases 8 and 9, loss of mitochondrial membrane potential, and cytochrome c release. Characteristically, antiapoptotic mediators such as Mcl-1, XIAP, survivin, and c-FLIP were downregulated. Consistent with its crit. function, c-FLIP overexpression resulted in a significant decrease of SAHA-mediated apoptosis. Enhanced sensitivity to TRAIL (TNF-related apoptosis-inducing ligand) and enhanced TRAIL signaling was seen in CTCL cell lines with high sensitivity, whereas cell lines with moderate response were characterized by downregulation of TRAIL-R2 and weaker TRAIL expression. Comparable proapoptotic responses to SAHA and to the combination with TRAIL were seen in ex vivo tumor T cells of CTCL patients. Thus, activation of extrinsic apoptosis pathways, related to c-FLIP downregulation and enhanced TRAIL signaling, appeared as characteristic for CTCL cell responsiveness to SAHA. An improved understanding of the pathways may facilitate its targeted use and the selection of suitable combinations.
- 38Sung, E. S.; Kim, A.; Park, J. S.; Chung, J.; Kwon, M. H.; Kim, Y. S. Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells. Apoptosis 2010, 15, 1256– 1269, DOI: 10.1007/s10495-010-0521-9[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1aqtLvF&md5=653c41ac58b241f38d88850ef7e2440bHistone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cellsSung, Eun-Sil; Kim, Aeyung; Park, Joon Seong; Chung, Junho; Kwon, Myung-Hee; Kim, Yong-SungApoptosis (2010), 15 (10), 1256-1269CODEN: APOPFN; ISSN:1360-8185. (Springer)Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several anti-apoptotic proteins (c-FLIP, Bcl-2, Bcl-XL, XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a crit. step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.
- 39Shankar, S.; Singh, T. R.; Fandy, T. E.; Luetrakul, T.; Ross, D. D.; Srivastava, R. K. Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. Int. J. Mol. Med. 2005, 16, 1125– 1138, DOI: 10.3892/ijmm.16.6.1125[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlWrt7zE&md5=2a7597bf3e9666159a8e355a7d4a5b0dInteractive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathwaysShankar, Sharmila; Singh, Thiyam R.; Fandy, Tamer E.; Luetrakul, Thitidaj; Ross, Douglas D.; Srivastava, Rakesh K.International Journal of Molecular Medicine (2005), 16 (6), 1125-1138CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.
- 40Insinga, A.; Monestiroli, S.; Ronzoni, S.; Gelmetti, V.; Marchesi, F.; Viale, A.; Altucci, L.; Nervi, C.; Minucci, S.; Pelicci, P. G. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat. Med. 2005, 11, 71– 76, DOI: 10.1038/nm1160[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FgvFeitw%253D%253D&md5=b6a5382cfb91cb583c0efee7c9e44bfcInhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathwayInsinga Alessandra; Monestiroli Silvia; Ronzoni Simona; Gelmetti Vania; Marchesi Francesco; Viale Andrea; Altucci Lucia; Nervi Clara; Minucci Saverio; Pelicci Pier GiuseppeNature medicine (2005), 11 (1), 71-6 ISSN:1078-8956.Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
- 41McCann, C.; Crawford, N.; Majkut, J.; Holohan, C.; Armstrong, C. W. D.; Maxwell, P. J.; Ong, C. W.; LaBonte, M. J.; McDade, S. S.; Waugh, D. J.; Longley, D. B. Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists. Cell Death Dis. 2018, 9, 1081, DOI: 10.1038/s41419-018-1125-5[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvitFWntQ%253D%253D&md5=b5a534af3156f34e24763b2a43253570Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonistsMcCann Christopher; Crawford Nyree; Majkut Joanna; Holohan Caitriona; Armstrong Chris W D; Maxwell Pamela J; Ong Chee Wee; LaBonte Melissa J; McDade Simon S; Waugh David J; Longley Daniel BCell death & disease (2018), 9 (11), 1081 ISSN:.Expression of tumor necrosis factor-α (TNFα) in the serum of prostate cancer patients is associated with poorer outcome and progression to castrate-resistant (CRPC) disease. TNFα promotes the activity of NFκB, which regulates a number of anti-apoptotic and proinflammatory genes, including those encoding the inhibitor of apoptosis proteins (IAPs); however, in the presence of IAP antagonists, TNFα can induce cell death. In the presence of recombinant or macrophage-derived TNFα, we found that IAP antagonists triggered degradation of cIAP1 and induced formation of Complex-IIb, consisting of caspase-8, FADD and RIPK1 in CRPC models; however, no, or modest levels of apoptosis were induced. This resistance was found to be mediated by both the long (L) and short (S) splice forms of the caspase-8 inhibitor, FLIP, another NFκB-regulated protein frequently overexpressed in CRPC. By decreasing FLIP expression at the post-transcriptional level in PC3 and DU145 cells (but not VCaP), the Class-I histone deacetylase (HDAC) inhibitor Entinostat promoted IAP antagonist-induced cell death in these models in a manner dependent on RIPK1, FADD and Caspase-8. Of note, Entinostat primarily targeted the nuclear rather than cytoplasmic pool of FLIP(L). While the cytoplasmic pool of FLIP(L) was highly stable, the nuclear pool was more labile and regulated by the Class-I HDAC target Ku70, which we have previously shown regulates FLIP stability. The efficacy of IAP antagonist (TL32711) and Entinostat combination and their effects on cIAP1 and FLIP respectively were confirmed in vivo, highlighting the therapeutic potential for targeting IAPs and FLIP in proinflammatory CRPC.
- 42Robert, C.; Rassool, F. V. HDAC inhibitors: roles of DNA damage and repair. Adv. Cancer Res. 2012, 116, 87– 129, DOI: 10.1016/B978-0-12-394387-3.00003-3[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Cgsb4%253D&md5=12be09097e3208dbf4840549ecae1efeHDAC inhibitors: roles of DNA damage and repairRobert, Carine; Rassool, Feyruz V.Advances in Cancer Research (2012), 116 (Histone Deacetylase Inhibitors as Cancer Therapeutics), 87-129CODEN: ACRSAJ; ISSN:0065-230X. (Elsevier Inc.)A review. Histone deacetylase inhibitors (HDACis) increase gene expression through induction of histone acetylation. However, it remains unclear whether specific gene expression changes det. the apoptotic response following HDACis administration. Herein, we discuss evidence that HDACis trigger in cancer and leukemia cells not only widespread histone acetylation but also actual increases in reactive oxygen species (ROS) and DNA damage that are further increased following treatment with DNA-damaging chemotherapies. While the origins of ROS prodn. are not completely understood, mechanisms, including inflammation and altered antioxidant signaling, have been reported. While the generation of ROS is an explanation, at least in part, for the source of DNA damage obsd. with HDACi treatment, DNA damage can also be independently induced by changes in the DNA repair activity and chromatin remodeling factors. Recent development of sirtuin inhibitors (SIRTis) has shown that, similar to HDACis, these drugs induce increases in ROS and DNA damage used singly, or in combination with HDACis and other drugs. Thus, induction of apoptosis by HDACis/SIRTis may result through oxidative stress and DNA damage mechanisms in addn. to direct activation of apoptosis-inducing genes. Nevertheless, while DNA damage and stress responses could be of interest as markers for clin. responses, they have yet to be validated as markers for responses to HDACi treatment in clin. trials, alone, and in combination.
- 43Petruccelli, L. A.; Dupere-Richer, D.; Pettersson, F.; Retrouvey, H.; Skoulikas, S.; Miller, W. H., Jr Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. PLoS One 2011, 6, e20987 DOI: 10.1371/journal.pone.0020987[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvVSisLg%253D&md5=083e63c00782a7d050d68d5e5b99e487Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cellsPetruccelli, Luca A.; Dupere-Richer, Daphne; Pettersson, Filippa; Retrouvey, Helene; Skoulikas, Sophia; Miller, Wilson H., Jr.PLoS One (2011), 6 (6), e20987CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clin. relevant concns., vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Addnl., AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a redn. in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents.
- 44Wasim, L.; Chopra, M. Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cells. Biomed. Pharmacother. 2016, 84, 1393– 1405, DOI: 10.1016/j.biopha.2016.10.057[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsLbE&md5=af85e5121fa4a7de551e5a9a07a75e06Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cellsWasim, Lubna; Chopra, MadhuBiomedicine & Pharmacotherapy (2016), 84 (), 1393-1405CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Cervical cancer is the fourth major cause of cancer-related deaths in women worldwide and is the most common cancer in developing countries. Therefore, a search for novel treatment modalities is warranted. The present study is designed to investigate the effect of pan histone deacetylase inhibitor, 'panobinostat', on cervical cancer cells alone and in combination with topoisomerase inhibitors. We assessed the effect of panobinostat on two cervical cancer cell lines, HeLa and SiHa, for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. The results indicate that panobinostat reduces the viability of cervical cancer cells in a dose- and time-dependent manner; it arrests HeLa cells in G0/G1 and SiHa cells in G2/M phase of the cell cycle. Panobinostat induced apoptosis through an increase in the ROS prodn. and the disruption of mitochondrial membrane potential. Concomitantly the expression of anti-apoptotic gene Bcl-xL was reduced, while levels of CDK inhibitor p21 and caspase-9 were increased. Panobinostat increased the acetylation of histone H3 indicating HDAC inhibition. In addn., panobinostat also showed synergistic effect with topoisomerase inhibitors mediated by increased activation of caspase-3/7 activity compared to that in cells treated with panobinostat alone. These results suggest a combination therapy using inhibitors of histone deacetylase and topoisomerase together could hold the promise for an effective targeted therapeutic strategy.
- 45Gaymes, T. J.; Padua, R. A.; Pla, M.; Orr, S.; Omidvar, N.; Chomienne, C.; Mufti, G. J.; Rassool, F. V. Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis?. Mol. Cancer Res. 2006, 4, 563– 573, DOI: 10.1158/1541-7786.MCR-06-0111[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XotV2rt7k%253D&md5=72fe7783bf624402a851a1565cdea3d8Histone Deacetylase Inhibitors (HDI) Cause DNA Damage in Leukemia Cells: A Mechanism for Leukemia-Specific HDI-Dependent Apoptosis?Gaymes, Terry J.; Padua, Rose Ann; Pla, Marika; Orr, Stephen; Omidvar, Nader; Chomienne, Christine; Mufti, Ghulam J.; Rassool, Feyruz V.Molecular Cancer Research (2006), 4 (8), 563-573CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events det. the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis.
- 46Yuan, Z.; Chen, S.; Sun, Q.; Wang, N.; Li, D.; Miao, S.; Gao, C.; Chen, Y.; Tan, C.; Jiang, Y. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy. Bioorg. Med. Chem. 2017, 25, 4100– 4109, DOI: 10.1016/j.bmc.2017.05.058[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpslGntbY%253D&md5=ac79d6e4d730eeefc1eda749823c80d5Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapyYuan, Zigao; Chen, Shaopeng; Sun, Qinsheng; Wang, Ning; Li, Dan; Miao, Shuangshuang; Gao, Chunmei; Chen, Yuzong; Tan, Chunyan; Jiang, YuyangBioorganic & Medicinal Chemistry (2017), 25 (15), 4100-4109CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivs. of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compds. showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compd. P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compds. targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
- 47Konsoula, Z.; Cao, H.; Velena, A.; Jung, M. Adamantanyl-histone deacetylase inhibitor H6CAHA exhibits favorable pharmacokinetics and augments prostate cancer radiation sensitivity. Int. J. Radiat. Oncol., Biol., Phys. 2011, 79, 1541– 1548, DOI: 10.1016/j.ijrobp.2010.11.057[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjs1SmtLc%253D&md5=223920498e20aede3b56ddc5b35a3768Adamantanyl-Histone Deacetylase Inhibitor H6CAHA Exhibits Favorable Pharmacokinetics and Augments Prostate Cancer Radiation SensitivityKonsoula, Zacharoula; Cao, Hong; Velena, Alfredo; Jung, MiraInternational Journal of Radiation Oncology, Biology, Physics (2011), 79 (5), 1541-1548CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: To evaluate pharmacol. properties of H6CAHA, an adamantyl-hydroxamate histone deacetylase inhibitor, and to investigate its effect on prostate cancer cells following exposure to γ-radiation in vitro and in vivo. Methods and Materials: H6CAHA was assessed for in vitro soly., lipophilicity and growth inhibition, and in vivo plasma pharmacokinetics. The effect of H6CAHA on radiation clonogenic survival and DNA damage repair was evaluated in human prostate cancer (PC3, DU145, LNCaP) and nonmalignant control epithelial (RWPE1 and 267B1) cell lines. The effect of this agent on the growth of prostate cancer xenografts was also assessed in mice. Results: H6CAHA demonstrated good soly. and permeability profiles and preferentially inhibited the growth of prostate cancer cells over nonmalignant cells. Plasma pharmacokinetics revealed that the area under the curve of H6CAHA was 8.08 ± 0.91 μM × h, and its half-life was 11.17 ± 0.87 h. Radiation clonogenic assays revealed that H6CAHA decreased the survival of prostate cancer cells at the dose that exerted limited effect on normal cells. Concomitantly, delayed DNA damage repair following combination treatment was evident in cancer cells, indicated by the prolonged appearance of γH2AX and Rad51 foci and suppression of DNA damage repair genes (ATM, BRCA1, and BRCA2). Combined modality of H6CAHA (daily i.p. injections for 10 days) with γ-radiation (10 × 2 Gy) completely blocked the growth of PC3 tumor xenografts (p < 0.001) over 60 days. Conclusion: These results support the potential therapeutic value of H6CAHA in combination with radiation and support the rationale for further clin. investigation.
- 48Adimoolam, S.; Sirisawad, M.; Chen, J.; Thiemann, P.; Ford, J. M.; Buggy, J. J. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 19482– 19487, DOI: 10.1073/pnas.0707828104[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVOhtQ%253D%253D&md5=09dd875fb60189a663e727ba0e973954HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombinationAdimoolam, Shanthi; Sirisawad, Mint; Chen, Jun; Thiemann, Patti; Ford, James M.; Buggy, Joseph J.Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (49), 19482-19487CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylase (HDAC) inhibitors such as the Ph hydroxamic acid PCI-24781 have emerged recently as a class of therapeutic agents for the treatment of cancer. Recent data showing synergy of HDAC inhibitors with ionizing radiation and other DNA-damaging agents have suggested that HDAC inhibitors may act, in part, by inhibiting DNA repair. Here the authors present evidence that HDAC enzymes are important for homologous recombinational repair of DNA double-strand breaks. Combination studies of PCI-24781 with the poly(ADP-ribose) polymerase inhibitor PJ34, an agent thought to produce lesions repaired by homologous recombination (HR), resulted in a synergistic effect on apoptosis. Immunofluorescence anal. demonstrated that HDAC inhibition caused a complete inhibition of subnuclear repair foci in response to ionizing radiation. Mechanistic investigations revealed that inhibition of HDAC enzymes by PCI-24781 led to a significant redn. in the transcription of genes specifically assocd. with HR, including RAD51. RAD51 protein levels were significantly decreased after 24 h of drug exposure both in vitro and in vivo. Consistent with inhibition of HR, treatment with PCI-24781 resulted in a decreased ability to perform homol. directed repair of I-Scel-induced chromosome breaks in transfected CHO cells. In addn., an enhancement of cell killing was obsd. in Ku mutant cells lacking functional nonhomologous end joining compared with WT cells. Together these results demonstrate that HDAC enzymes are critically important to enable functional HR by controlling the expression of HR-related genes and promoting the proper assembly of HR-directed subnuclear foci.
- 49Munshi, A.; Kurland, J. F.; Nishikawa, T.; Tanaka, T.; Hobbs, M. L.; Tucker, S. L.; Ismail, S.; Stevens, C.; Meyn, R. E. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin. Cancer Res. 2005, 11, 4912– 4922, DOI: 10.1158/1078-0432.CCR-04-2088[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVGgsb8%253D&md5=fb3d905f585b207347b4fc4bf1aecf1eHistone Deacetylase Inhibitors Radiosensitize Human Melanoma Cells by Suppressing DNA Repair ActivityMunshi, Anupama; Kurland, John F.; Nishikawa, Takashi; Tanaka, Toshimitsu; Hobbs, Marvette L.; Tucker, Susan L.; Ismail, Sheikh; Stevens, Craig; Meyn, Raymond E.Clinical Cancer Research (2005), 11 (13), 4912-4922CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Histone deacetylase (HDAC) inhibitors have emerged recently as promising anticancer agents. They arrest cells in the cell cycle and induce differentiation and cell death. The antitumor activity of HDAC inhibitors has been linked to their ability to induce gene expression through acetylation of histone and nonhistone proteins. However, it has recently been suggested that HDAC inhibitors may also enhance the activity of other cancer therapeutics, including radiotherapy. The purpose of this study was to evaluate the ability of HDAC inhibitors to radiosensitize human melanoma cells in vitro. Exptl. Design: A panel of HDAC inhibitors that included sodium butyrate (NaB), phenylbutyrate, tributyrin, and trichostatin A were tested for their ability to radiosensitize two human melanoma cell lines (A375 and MeWo) using clonogenic cell survival assays. Apoptosis and DNA repair were measured by std. assays. RESULTS: NaB induced hyperacetylation of histone H4 in the two melanoma cell lines and the normal human fibroblasts. NaB radiosensitized both the A375 and MeWo melanoma cell lines, substantially reducing the surviving fraction at 2 Gy (SF2), whereas it had no effect on the normal human fibroblasts. The other HDAC inhibitors, phenylbutyrate, tributyrin, and trichostatin A had significant radiosensitizing effects on both melanoma cell lines tested. NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as detd. based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examd. γ-H2AX phosphorylation as a marker of radiation response to NaB and obsd. that compared with controls, γ-H2AX foci persisted long after ionizing exposure in the NaB-treated cells. CONCLUSIONS: HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that γ-H2AX phosphorylation can be used as a predictive marker of radioresponse.
- 50Lu, Y. S.; Chou, C. H.; Tzen, K. Y.; Gao, M.; Cheng, A. L.; Kulp, S. K.; Cheng, J. C. Radiosensitizing effect of a phenylbutyrate-derived histone deacetylase inhibitor in hepatocellular carcinoma. Int. J. Radiat. Oncol., Biol., Phys. 2012, 83, e181 DOI: 10.1016/j.ijrobp.2011.12.022[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1agurs%253D&md5=8749674a78d62e0b702dcdb674a1612fRadiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular CarcinomaLu, Yen-Shen; Chou, Chia-Hung; Tzen, Kai-Yuan; Gao, Ming; Cheng, Ann-Lii; Kulp, Samuel K.; Cheng, Jason Chia-HsienInternational Journal of Radiation Oncology, Biology, Physics (2012), 83 (2), e181-e189CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect assocs. with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradn. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, resp. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was obsd. in Huh-7 orthotopic model of tumor growth by 52% and 82%, resp. This tumor suppression was assocd. with inhibition of intratumoral Ku70 activity as well as redns. in markers of HDAC activity and proliferation, and increased apoptosis. AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.
- 51Butler, L. M.; Zhou, X.; Xu, W. S.; Scher, H. I.; Rifkind, R. A.; Marks, P. A.; Richon, V. M. The histone deacetylase inhibitor SAHA arrests cancer cell growth, upregulates thioredoxin-binding protein-2 and downregulates thioredoxin. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 11700– 11705, DOI: 10.1073/pnas.182372299[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XntFWqsbY%253D&md5=5930aacd5ff4ac0383fadf84cbf1d98eThe histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxinButler, Lisa M.; Zhou, Xianbo; Xu, Wei-Sheng; Scher, Howard I.; Rifkind, Richard A.; Marks, Paul A.; Richon, Victoria M.Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (18), 11700-11705CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clin. trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-upregulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.
- 52Deroanne, C. F.; Bonjean, K.; Servotte, S.; Devy, L.; Colige, A.; Clausse, N.; Blacher, N.; Verdin, E.; Foidart, J. M.; Nusgens, B. V.; Castronovo, V. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002, 21, 427– 436, DOI: 10.1038/sj.onc.1205108[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVygtL4%253D&md5=6c29afb901cdf1ee5a31b144199b4e36Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signalingDeroanne, Christophe F.; Bonjean, Karine; Servotte, Sandrine; Devy, Laetitia; Colige, Alain; Clausse, Nathalie; Blacher, Sylvia; Verdin, Eric; Foidart, Jean-Michel; Nusgens, Betty V.; Castronovo, VincentOncogene (2002), 21 (3), 427-436CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)Angiogenesis is a complex biol. process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-pos. capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relation, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not obsd. in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.
- 53Hutt, D. M.; Roth, D. M.; Vignaud, H.; Cullin, C.; Bouchecareilh, M. The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition. PLoS One 2014, 9, e106224 DOI: 10.1371/journal.pone.0106224
- 54Kim, M. S.; Kwon, H. J.; Lee, Y. M.; Baek, J. H.; Jang, J. E.; Lee, S. W.; Moon, E. J.; Kim, H. S.; Lee, S. K.; Chung, H. Y.; Kim, C. W.; Kim, K. W. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat. Med. 2001, 7, 437– 443, DOI: 10.1038/86507[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXis1yks7s%253D&md5=cd7462043c77421e07b4c148207267c9Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genesKim, Myoung Sook; Kwon, Ho Jeong; Lee, You Mie; Baek, Jin Hyen; Jang, Jae-Eun; Lee, Sae-Won; Moon, Eun-Joung; Kim, Hae-Sun; Lee, Seok-Ki; Chung, Hae Young; Kim, Chul Woo; Kim, Kyu-WonNature Medicine (New York, NY, United States) (2001), 7 (4), 437-443CODEN: NAMEFI; ISSN:1078-8956. (Nature America Inc.)Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1α and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.
- 55Crazzolara, R.; Jöhrer, K.; Johnstone, R. W.; Greil, R.; Ofler, R.; Meister, B.; Bernhard, D. Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia. Br. J. Haematol. 2002, 119, 965– 969, DOI: 10.1046/j.1365-2141.2002.03955.x[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt12nuw%253D%253D&md5=0c5b12b74a00b150900e421a9e2ad1c6Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukemiaCrazzolara, Roman; Johrer, Karin; Johnstone, Ricky W.; Greil, Richard; Kofler, Reinhard; Meister, Bernhard; Bernhard, DavidBritish Journal of Haematology (2002), 119 (4), 965-969CODEN: BJHEAL; ISSN:0007-1048. (Blackwell Science Ltd.)The chemokine receptor CXCR4 plays a crucial role in the survival and trafficking of leukemia cells and requires further attention as human immunodeficiency virus type I (HIV-I) utilizes CXCR4 as the major coreceptor for cellular entry. We demonstrated that inhibitors of histone deacetylases, currently being tested in clin. trials for the treatment of various tumors, extensively downregulated CXCR4 protein and mRNA levels in leukemia cell lines and lymphoblasts from patients with childhood acute leukemia. As a result, the ability of stromal cell-derived factor-1 to induce cellular migration was impaired. Repression of CXCR4 transcription by inhibitors of histone deacetylases might therefore represent a promising novel approach in the treatment of acute leukemias.
- 56Magner, W. J.; Kazim, A. L.; Stewart, C.; Romano, M. A.; Catalano, G.; Grande, C.; Keiser, N.; Santaniello, F.; Tomasi, B. T. Activation of MHC class I, II and CD40 gene expression by histone deacetylase inhibitors. J. Immunol. 2000, 165, 7017– 7024, DOI: 10.4049/jimmunol.165.12.7017[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFygsrs%253D&md5=99a484093103f963af0075000758055eActivation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitorsMagner, William J.; Kazim, A. Latif; Stewart, Carleton; Romano, Michelle A.; Catalano, Geoffrey; Grande, Catherine; Keiser, Nicholas; Santaniello, Frank; Tomasi, Thomas B.Journal of Immunology (2000), 165 (12), 7017-7024CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Epigenetic mechanisms are involved in regulating chromatin structure and gene expression through repression. In this study, we show that histone deacetylase inhibitors (DAIs) that alter the acetylation of histones in chromatin enhance the expression of several genes on tumor cells including: MHC class I, II, and the costimulatory mol. CD40. Enhanced transcription results in a significant increase in protein expression on the tumor cell surface, and expression can be elicited on some tumors that are unresponsive to IFN-γ. The magnitude of induction of these genes cannot be explained by the effect of DAIs on the cell cycle or enhanced apoptosis. Induction of class II genes by DAIs was accompanied by activation of a repressed class II transactivator gene in a plasma cell tumor but, in several other tumor cell lines, class II was induced in the apparent absence of class II transactivator transcripts. These findings also suggest that the abnormalities obsd. in some tumors in the expression of genes crit. to tumor immunity may result from epigenetic alterations in chromatin and gene regulation in addn. to well-established mutational mechanisms.
- 57Maeda, T.; Towatari, M.; Kosugi, H.; Saito, H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 2000, 96, 3847– 3856, DOI: 10.1182/blood.V96.12.3847[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXosVGntbk%253D&md5=1f6dd50e56a0c4104447a3243de5627dUp-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cellsMaeda, Takahiro; Towatari, Masayuki; Kosugi, Hiroshi; Saito, HidehikoBlood (2000), 96 (12), 3847-3856CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Histone deacetylase inhibitors (HDACIs) have been used to focus on the effects of inducing gene expression through the acetylation of histones which results in chromatin remodeling. The study explored whether HDACIs could induce the expression of costimulatory/adhesion mols. on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. The expression of CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, and intracellular adhesion mol.-1 (ICAM-1) was tested in human AML cell lines after the addn. of HDACI, sodium butyrate (SB). Generally, increased expression of CD86 was obsd. by SB treatment in a majority of cell lines, and ICAM-1 was expressed in fewer cell lines. Essentially the same results were obtained using other HDACIs such as FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 accompanied with RNA synthesis inhibition assay and nuclear run-on assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunopptn. expts. showed that HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In 30 clin. AML samples, CD86 expression was significantly increased (P <.001) by SB treatment, and the expression of HLA-DR and ICAM-1 was moderately increased (P <.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold compared with allo-MLR obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML.
- 58Li, S.; Fossati, G.; Marchetti, C.; Modena, D.; Pozzi, P.; Reznikov, L. L.; Moras, M. L.; Azam, T.; Abbate, A.; Mascagni, P.; Dinarello, C. A. Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. J. Biol. Chem. 2015, 290, 2368– 2378, DOI: 10.1074/jbc.M114.618454[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCqtbs%253D&md5=1af57c4a219c0636e77fa1be3f7a98b4Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in VivoLi, Suzhao; Fossati, Gianluca; Marchetti, Carlo; Modena, Daniela; Pozzi, Pietro; Reznikov, Leonid L.; Moras, Maria Luisa; Azam, Tania; Abbate, Antonio; Mascagni, Paolo; Dinarello, Charles A.Journal of Biological Chemistry (2015), 290 (4), 2368-2378CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)ITF2357 (generic givinostat) is an orally active, hydroxamic-contg. histone deacetylase (HDAC) inhibitor with broad anti-inflammatory properties, which has been used to treat children with systemic juvenile idiopathic arthritis. ITF2357 inhibits both Class I and II HDACs and reduces caspase-1 activity in human peripheral blood mononuclear cells and the secretion of IL-1β and other cytokines at 25-100 nm; at concns. >200 nm, ITF2357 is toxic in vitro. ITF3056, an analog of ITF2357, inhibits only HDAC8 (IC50 of 285 nm). Here we compared the prodn. of IL-1β, IL-1α, TNFα, and IL-6 by ITF2357 with that of ITF3056 in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), heat-killed Candida albicans, or anti-CD3/anti-CD28 antibodies. ITF3056 reduced LPS-induced cytokines from 100 to 1000 nm; at 1000 nm, the secretion of IL-1β was reduced by 76%, secretion of TNFα was reduced by 88%, and secretion of IL-6 was reduced by 61%. The intracellular levels of IL-1α were 30% lower. There was no evidence of cell toxicity at ITF3056 concns. of 100-1000 nm. Gene expression of TNFα was markedly reduced (80%), whereas IL-6 gene expression was 40% lower. Although anti-CD3/28 and Candida stimulation of IL-1β and TNFα was modestly reduced, IFNγ prodn. was 75% lower. Mechanistically, ITF3056 reduced the secretion of processed IL-1β independent of inhibition of caspase-1 activity; however, synthesis of the IL-1β precursor was reduced by 40% without significant decrease in IL-1β mRNA levels. In mice, ITF3056 reduced LPS-induced serum TNFα by 85% and reduced IL-1β by 88%. These data suggest that specific inhibition of HDAC8 results in reduced inflammation without cell toxicity.
- 59Leoni, F.; Zaliani, A.; Bertolini, G.; Porro, G.; Pagani, P.; Pozzi, P.; Donà, G.; Fossati, G.; Sozzani, S.; Azam, T.; Bufler, P.; Fantuzzi, G.; Goncharov, I.; Kim, S. H.; Pomerantz, B. J.; Reznikov, L. L.; Siegmund, B.; Dinarello, C. A.; Mascagni, P. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 2995– 3000, DOI: 10.1073/pnas.052702999[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xit1Cru78%253D&md5=f3d5aa94ba911a071246527199c563aeThe antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokinesLeoni, Flavio; Zaliani, Andrea; Bertolini, Giorgio; Porro, Giulia; Pagani, Paolo; Pozzi, Pietro; Dona, Giancarlo; Fossati, Gianluca; Sozzani, Silvano; Azam, Tania; Bufler, Philip; Fantuzzi, Giamila; Goncharov, Igor; Kim, Soo-Hyun; Pomerantz, Benjamin J.; Reznikov, Leonid L.; Siegmund, Britta; Dinarello, Charles A.; Mascagni, PaoloProceedings of the National Academy of Sciences of the United States of America (2002), 99 (5), 2995-3000CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-contg. hybrid polar mol.; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the prodn. of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1β, IL-12, and IFN-γ (50% redn. at 100-200 nM). The prodn. of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addn., IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyper-acetylate other targets.
- 60Shao, Y.; Gao, Z.; Marks, P. A.; Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 18030– 18035, DOI: 10.1073/pnas.0408345102[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsl2nsQ%253D%253D&md5=50d75dc3fafd03181c5d19365d2b605fApoptotic and autophagic cell death induced by histone deacetylase inhibitorsShao, Yufang; Gao, Zhonghua; Marks, Paul A.; Jiang, XuejunProceedings of the National Academy of Sciences of the United States of America (2004), 101 (52), 18030-18035CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bcl-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bcl-XL, and pharmacol. inhibition of caspase activity did not prevent SAHA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphol. features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clin. implications in treating cancers with apoptotic defects.
- 61Condorelli, F.; Gnemmi, I.; Vallario, A.; Genazzani, A. A.; Canonico, P. L. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br. J. Pharmacol. 2008, 153, 657– 668, DOI: 10.1038/sj.bjp.0707608[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVKjsr8%253D&md5=afb61167f7671c707f498c8b571b736dInhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cellsCondorelli, F.; Gnemmi, I.; Vallario, A.; Genazzani, A. A.; Canonico, P. L.British Journal of Pharmacology (2008), 153 (4), 657-668CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Inhibitors of histone deacetylase (HDAC) are emerging as a promising class of anti-cancer drugs, but a generic deregulation of transcription in neoplastic cells cannot fully explain their therapeutic effects. In this study we evaluated alternative mol. mechanisms by which HDAC inhibitors could affect neuroblastoma viability. Effects of HDAC inhibitors on survival of the I-type SK-N-BE and the N-type NB SH-SY5Y neuroblastoma cell lines were assessed by the MTT assay. Mol. pathways leading to this were examd. by western blot, confocal microscopy and cytofluorometry. The mRNA levels of apoptotic mediators were assessed semi-quant. by RT-PCR. Tumor-suppressor p53 trans activity was assessed in EMSA expts. HDAC inhibitors were also studied in cells subjected to plasmid-based p53 interference (p53i). HDAC inhibitors induced cell death via the mitochondrial pathway of apoptosis with recruitment of Bcl-2 family members. Bcl-2 overexpression rendered neuroblastoma cells resistant to HDAC inhibitor treatment. Low concns. of HDAC inhibitors (0.9 m) caused a G2 cell-cycle arrest and a marked upregulation of the p21/Waf1/Cip1 protein. HDAC inhibitors also activate the p53 protein via hyper-acetylation and nuclear re-localization, without affecting its protein expression. Accordingly, HDAC inhibitor-induced cell-killing and p21/Waf1/Cip1 upregulation is impaired in p53i-cells. In neuroblastoma cells, HDAC inhibitors may overcome the resistance to classical chemotherapeutic drugs by restoring the p53 tumor-repressor function via its hyper-acetylation and nuclear migration, events usually impaired in such tumors. In neuroblastoma cells, HDAC inhibitors are not able to induce p21/Waf1/Cip1 in the absence of a functional p53.
- 62Li, Z. Y.; Li, Q. Z.; Chen, L.; Chen, B. D.; Wang, B.; Zhang, X. J.; Li, W. P. Histone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance by Blocking NF-κB-Dependent Transcription in Glioblastoma Cell Lines. Neurochem. Res. 2016, 41, 3192– 3205, DOI: 10.1007/s11064-016-2043-5[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyksL7K&md5=f332f2ea76c8170814d0b8432cdc028eHistone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance by Blocking NF-κB-Dependent Transcription in Glioblastoma Cell LinesLi, Zong-yang; Li, Qing-zhong; Chen, Lei; Chen, Bao-dong; Wang, Bo; Zhang, Xie-jun; Li, Wei-pingNeurochemical Research (2016), 41 (12), 3192-3205CODEN: NEREDZ; ISSN:0364-3190. (Springer)Glioblastoma (GBM) is the most frequent and aggressive tumor in the central nervous system. Many studies have demonstrated that upregulation of the NF-κB onco-pathway is accompanied by the acquisition of Temozolomide (TMZ) resistance in GBM cells. Here, we show that RGFP109, a selective histone deacetylase (HDAC1 and HDAC3) inhibitor, overcomes TMZ resistance and downregulates the expression of NF-κB-regulated pro-survival genes in a TMZ-resistant (TR) GBM cell line. RGFP109 did not alter the phosphorylation levels of NF-κB/p65 or inhibitory κBα (IκBα). Immunofluorescence microscopy showed that RGFP109 does not block the nuclear translocation of NF-κB/p65. However, co-immunopptn. assays revealed that RGFP109 induces the hyperacetylation of NF-κB/p65 and histones, and blocks interactions between NF-κB/p65 and its coactivators, p300 and p300/CBP-assocd. factor (PCAF). These results indicate that RGFP109-mediated post-translational nuclear acetylation may be involved in the regulation of NF-κB. Electrophoretic mobility shift assays revealed that RGFP109 reduces NF-κB/p65 binding to κB-DNA and decreased the transcriptional level of κB-mediated genes, suggesting that RGFP109-induced hyperacetylation leads to attenuated transcription of the κB gene. In addn., RGFP109 elevates the expression of inhibitor of growth 4 (ING4), which is typically downregulated in GBM cells. Importantly, we found that RGFP109 enhances ING4 recognition and binding to NF-κB/p65, which may be pos. correlated with reduced interactions between NF-κB/p65 and p300/PCAF, thereby effecting transcription of the κB gene. Finally, we show that knockdown of ING4 with plasmids contg. pcDNA3.1-ING4 shRNA abolished the effect of RGFP109. Therefore, ING4 may act as a corepressor and facilitate RGFP109-triggered suppression of the NF-κB pathway. Taken together, our data show that RGFP109, an HDAC inhibitor, in combination with TMZ may be a therapeutic candidate for patients with temozolomide-resistant GBM.
- 63Vishwakarma, S.; Iyer, L. R.; Muley, M.; Singh, P. K.; Shastry, A.; Saxena, A.; Kulathingal, J.; Vijaykanth, G.; Raghul, J.; Rajesh, N.; Rathinasamy, S.; Kachhadia, V.; Kilambi, N.; Rajgopal, S.; Balasubramanian, G.; Narayanan, S. Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int. Immunopharmacol. 2013, 16, 72– 78, DOI: 10.1016/j.intimp.2013.03.016[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlWjsr4%253D&md5=1810b101113330405d3923cbadb628b7Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effectsVishwakarma, Santosh; Iyer, Lakshmi R.; Muley, Milind; Singh, Pankaj Kumar; Shastry, Arun; Saxena, Ambrish; Kulathingal, Jayanarayan; Vijaykanth, G.; Raghul, J.; Rajesh, Navin; Rathinasamy, Suresh; Kachhadia, Virendra; Kilambi, Narasimhan; Rajgopal, Sridharan; Balasubramanian, Gopalan; Narayanan, ShridharInternational Immunopharmacology (2013), 16 (1), 72-78CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)Epigenetic modifications represent a promising new approach to modulate cell functions as obsd. in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that was obsd. with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is α-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM, resp. Addnl., Tubastatin inhibited NO secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 μM and induced α-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw vol. at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clin. scores (∼ 70%) by Tubastatin was confirmed histopathol. and was found comparable to dexamethasone (∼ 90% inhibition of clin. scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin.
- 64Leng, C.; Gries, M.; Ziegler, J.; Lokshin, A.; Mascagni, P.; Lentzsch, S.; Mapara, M. Y. Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp. Hematol. 2006, 34, 776– 787, DOI: 10.1016/j.exphem.2006.02.014[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvVyntLY%253D&md5=8f028bebfb0a4ca6198545fff17efa95Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1Leng, Corinna; Gries, Margarethe; Ziegler, Judy; Lokshin, Anna; Mascagni, Paolo; Lentzsch, Suzanne; Mapara, Markus Y.Experimental Hematology (New York, NY, United States) (2006), 34 (6), 776-787CODEN: EXHMA6; ISSN:0301-472X. (Elsevier Inc.)Histone deacetylase (HDAC) inhibitors reduce development of graft-vs.-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Administration of the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA) resulted in a significantly reduced GVHD-dependent mortality following fully major histocompatibility complex-mismatched allogeneic BMT. However, SAHA treatment did not affect T-cell activation or T-cell expansion in vitro and in vivo. Therefore, we focused on the effects of SAHA treatment on cytokine prodn. and intracellular signaling events in vitro and in vivo following GVHD induction. Cultivation in the presence of SAHA broadly inhibited lipopolysaccharide (LPS) and alloantigen-induced cytokine/chemokine prodn. in vitro and led also to a significant decrease in interferon-γ and tumor necrosis factor-α levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro. Induction of GVHD led to a rapid phosphorylation of STAT 1 in the liver and spleen, which was markedly reduced by SAHA treatment. In conclusion, GVHD is assocd. with a marked induction of phosphorylation of STAT1 in the liver and spleen, and SAHA-dependent redn. of GVHD is assocd. with systemic and local inhibition of phosphorylated STAT1 and blunting proinflammatory cytokine prodn. during the initiation phase of GVHD.
- 65Chen, J.; Li, N.; Liu, B.; Ling, J.; Yang, W.; Pang, X.; Li, T. Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways. Life Sci. 2020, 248, 117469, DOI: 10.1016/j.lfs.2020.117469[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1ersbo%253D&md5=27ee9f16af9375ba31a37612136d8ff4Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathwaysChen, Jing; Li, Na; Liu, Boxia; Ling, Jun; Yang, Wenjun; Pang, Xiufeng; Li, TaoLife Sciences (2020), 248 (), 117469CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)Histone deacetylases inhibitors have shown favorable antitumor activity in clin. investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying mol. mechanisms. MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the mol. mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 s.c. tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. Our results demonstrated that SB939 at 0.5-1μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
- 66Pinz, S.; Unser, S.; Buob, D.; Fischer, P.; Jobst, B.; Rascle, A. Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function. Nucleic Acids Res. 2015, 43, 3524– 3545, DOI: 10.1093/nar/gkv188[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFaisbjE&md5=b97274a797559912f296ab19fd7975e9Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein functionPinz, Sophia; Unser, Samy; Buob, Dominik; Fischer, Philipp; Jobst, Belinda; Rascle, AnneNucleic Acids Research (2015), 43 (7), 3524-3545CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)Signal transducer and activator of transcription STAT5 is essential for the regulation of proliferation and survival genes. Its activity is tightly regulated through cytokine signaling and is often upregulated in cancer. The authors showed previously that the deacetylase inhibitor trichostatin A (TSA) inhibits STAT5-mediated transcription by preventing recruitment of the transcriptional machinery at a step following STAT5 binding to DNA. The mechanism and factors involved in this inhibition remain unknown. The authors now show that deacetylase inhibitors do not target STAT5 acetylation, as the authors initially hypothesized. Instead, they induce a rapid increase in global histone acetylation apparently resulting in the delocalization of the bromodomain and extra-terminal (BET) protein Brd2 and of the Brd2-assocd. factor TBP to hyperacetylated chromatin. Treatment with the BET inhibitor (+)-JQ1 inhibited expression of STAT5 target genes, supporting a role of BET proteins in the regulation of STAT5 activity. Accordingly, chromatin immunopptn. demonstrated that Brd2 is assocd. with the transcriptionally active STAT5 target gene Cis and is displaced upon TSA treatment. The authors' data therefore indicate that Brd2 is required for the proper recruitment of the transcriptional machinery at STAT5 target genes and that deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function.
- 67Rascle, A.; Johnston, J. A.; Amati, B. Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol. Cell. Biol. 2003, 23, 4162– 4173, DOI: 10.1128/MCB.23.12.4162-4173.2003[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1ykurs%253D&md5=11bf35b090b67fe97b668fa11a410415Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5Rascle, Anne; Johnston, James A.; Amati, BrunoMolecular and Cellular Biology (2003), 23 (12), 4162-4173CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The signal transducer and activator of transcription STAT5 plays a major role in the cellular response to cytokines, but the mechanism by which it activates transcription remains poorly understood. We show here that deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and sodium butyrate) prevent induction of endogenous STAT5 target genes, implying that a deacetylase activity is required for that process. Microarray analyses revealed that this requirement is common to all STAT5 target genes. Using chromatin immunopptn., we show that, following STAT5 DNA binding, deacetylase inhibitors block transcription initiation by preventing recruitment of the basal transcription machinery. This inhibition is not due to effects on histone H3 and H4 acetylation or chromatin remodeling within the promoter region. This novel mechanism of transactivation by STAT5 provides a rationale for the use of deacetylase inhibitors for therapeutic intervention in STAT5-assocd. cancers.
- 68He, B.; Dai, L.; Zhang, X.; Chen, D.; Wu, J.; Feng, X.; Zhang, Y.; Xie, H.; Zhou, L.; Wu, J.; Zheng, S. The HDAC inhibitor quisinostat (JNJ-26481585) supresses hepatocellular carcinoma alone and synergistically in combination with sorafenib by G0/G1 phase arrest and apoptosis induction. Int. J. Biol. Sci. 2018, 14, 1845– 1858, DOI: 10.7150/ijbs.27661[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSntLbN&md5=3cab5f9dde8ea91a491a2381af18f050The HDAC inhibitor quisinostat (JNJ-26481585) suppresses hepatocellular carcinoma alone and synergistically in combination with sorafenib by G0/G1 phase arrest and apoptosis inductionHe, Bin; Dai, Longfei; Zhang, Xiaoqian; Chen, Diyu; Wu, Jingbang; Feng, Xiaode; Zhang, Yanpeng; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, ShusenInternational Journal of Biological Sciences (2018), 14 (13), 1845-1858CODEN: IJBSB9; ISSN:1449-2288. (Ivyspring International Publisher)In our study, we evaluated effect of quisinostat alone and in combination with sorafenib in HCC cells via inducing G0/G1 phase arrest through PI3K/AKT/p21 pathway and apoptosis by JNK/c-Jun/caspase3 pathway in vitro and in vivo. The proliferation assay and flow cytometry were used to measure the viability, cell cycle and apoptosis. Here, we found that quisinostat impeded cell proliferation, and remarkably induced G0/G1 phase arrest and apoptosis in HCC cells in a dose-dependent manner. G0/G1 phase arrest was obsd. by alterations in PI3K/AKT/p21 proteins. Meanwhile the JNK, c-jun and caspase-3 were activated by quisinostat in a dose-dependent manner. Correspondingly quisinostat facilitated G0/G1 cycle arrest and apoptosis in HCC cells through PI3K/AKT/p21 pathways and JNK/c- jun/caspase3 pathways. Moreover, the potent tumor-suppressive effects facilitated by quisinostat, was significantly potentiated by combination with sorafenib in vitro and vivo. The combination treatment of quisinostat and sorafenib markedly suppressed cell proliferation and induced apoptosis in a synergistic manner. Our study indicated that quisinostat, as a novel chemotherapy for HCC, exhibited excellent antitumor activity in vitro and vivo, which was even enhanced by the addn. of sorafenib, implying combination of quisinostat with sorafenib a promising and alternative therapy for patients with advanced hepatocellular carcinoma.
- 69Sharma, V.; Koul, N.; Joseph, C.; Dixit, D.; Ghosh, S.; Sen, E. HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J. Cell. Mol. Med. 2010, 14, 2151– 2561, DOI: 10.1111/j.1582-4934.2009.00844.x[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVahu77P&md5=b10dea0614f7fa1a5724e4b9129ea63eHDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activitySharma, Vivek; Koul, Nitin; Joseph, Christy; Dixit, Deobrat; Ghosh, Sadashib; Sen, ElloraJournal of Cellular and Molecular Medicine (2010), 14 (8), 2151-2161CODEN: JCMMC9; ISSN:1582-1838. (Wiley-Blackwell)The present study identified a novel mechanism of induction of apoptosis in glioblastoma cells by scriptaid - a histone deacetylase (HDAC) inhibitor. Scriptaid reduced glioma cell viability by increasing Jun N-terminal kinase (JNK) activation. Although scriptaid induced activation of both p38MAPK and JNK, it was the inhibition of JNK that attenuated scriptaid-induced apoptosis significantly. Scriptaid also increased the expression of (i) p21 and p27 involved in cell-cycle regulation and (ii) γH2AX assocd. with DNA damage response in a JNK-dependent manner. Treatment with scriptaid increased Ras activity in glioma cells, and transfection of cells with constitutively active RasV12 further sensitized glioma cells to scriptaid-induced apoptosis. Scriptaid also inhibited telomerase activity independent of JNK. Taken together, our findings indicate that scriptaid (i) induces apoptosis and reduces glioma cell proliferation by elevating JNK activation and (ii) also decreases telomerase activity in a JNK-independent manner.
- 70Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.; Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.; Boyapalle, S.; Atadja, P.; Seto, E.; Bhalla, K. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005, 280, 26729– 26734, DOI: 10.1074/jbc.C500186200[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmt1Ggs7w%253D&md5=0d634a576233827dc91d6b3044e56546Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitorsBali, Purva; Pranpat, Michael; Bradner, James; Balasis, Maria; Fiskus, Warren; Guo, Fei; Rocha, Kathy; Kumaraswamy, Sandhya; Boyapalle, Sandhya; Atadja, Peter; Seto, Edward; Bhalla, KapilJournal of Biological Chemistry (2005), 280 (29), 26729-26734CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The hydroxamic acid (HAA) analog pan-histone deacetylase (HDAC) inhibitors (HDIs) LAQ824 and LBH589 have been shown to induce acetylation and inhibit the ATP binding and chaperone function of heat shock protein (HSP) 90. This promotes the polyubiquitylation and degrdn. of the pro-growth and pro-survival client proteins Bcr-Abl, mutant FLT-3, c-Raf, and AKT in human leukemia cells. HDAC6 is a member of the class IIB HDACs. It is predominantly cytosolic, microtubule-assocd. α-tubulin deacetylase that is also known to promote aggresome inclusion of the misfolded polyubiquitylated proteins. Here the authors demonstrate that in the Bcr-abl oncogene expressing human leukemia K562 cells, HDAC6 can be coimmunopptd. with HSP90, and the knock-down of HDAC6 by its siRNA induced the acetylation of HSP90 and α-tubulin. Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone assocn. of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl. Conversely, the ectopic overexpression of HDAC6 inhibited LAQ824-induced acetylation of HSP90 and α-tubulin and reduced LAQ824-mediated depletion of Bcr-Abl, AKT, and c-Raf. Collectively, these findings indicate that HDAC6 is also an HSP90 deacetylase. Targeted inhibition of HDAC6 leads to acetylation of HSP90 and disruption of its chaperone function, resulting in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins including Bcr-Abl. Depletion of HDAC6 sensitized human leukemia cells to HAA-HDIs and proteasome inhibitors.
- 71Kovacs, J. J.; Murphy, P. J.; Gaillard, S.; Zhao, X.; Wu, J. T.; Nicchitta, C. V.; Yoshida, M.; Toft, D. O.; Pratt, W.; Yao, T. P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 2005, 18, 601– 607, DOI: 10.1016/j.molcel.2005.04.021[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltFOksb4%253D&md5=338a8456c56a74d82ad3d28cbccae33fHDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptorKovacs, Jeffrey J.; Murphy, Patrick J. M.; Gaillard, Stephanie; Zhao, Xuan; Wu, June-Tai; Nicchitta, Christopher V.; Yoshida, Minoru; Toft, David O.; Pratt, William B.; Yao, Tso-PangMolecular Cell (2005), 18 (5), 601-607CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)The mol. chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a crit. modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissocn. from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.
- 72Place, R. F.; Noonan, E. J.; Giardina, C. HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem. Pharmacol. 2005, 70, 394– 406, DOI: 10.1016/j.bcp.2005.04.030[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVWms7w%253D&md5=c2bb273b4516e1dcb19e7138022f8256HDAC inhibition prevents NF-κB activation by suppressing proteasome activity: Down-regulation of proteasome subunit expression stabilizes IκBαPlace, Robert F.; Noonan, Emily J.; Giardina, CharlesBiochemical Pharmacology (2005), 70 (3), 394-406CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)The short chain fatty acid (SCFA) butyrate (BA) and other histone deacetylase (HDAC) inhibitors can rapidly induce cell cycle arrest and differentiation of colon cancer cell lines. We found that butyrate and the specific HDAC inhibitor trichostatin A (TSA) can reprogram the NF-κB response in colon cancer cells. Specifically, TNF-α activation is suppressed in butyrate-differentiated cells, whereas IL-1β activation is largely unaffected. To gain insight into the relation between butyrate-induced differentiation and NF-κB regulation, we detd. the impact of butyrate on proteasome activity and subunit expression. Interestingly, butyrate and TSA reduced the cellular proteasome activity in colon cancer cell lines. The drop in proteasome activity results from the reduced expression of the catalytic β-type subunits of the proteasome at both the protein and mRNA level. The selective impact of HDAC inhibitors on TNF-α-induced NF-κB activation appears to relate to the fact that the TNF-α-induced activation of NF-κB is mediated by the proteasome, whereas NF-κB activation by IL-1β is largely proteasome-independent. These findings indicate that cellular differentiation status and/or proliferative capacity can significantly impact proteasome activity and selectively alter NF-κB responses in colon cancer cells. This information may be useful for the further development and targeting of HDAC inhibitors as anti-neoplastic and anti-inflammatory agents.
- 73Fotheringham, S.; Epping, M. T.; Stimson, L.; Khan, O.; Wood, V.; Pezzella, F.; Bernards, R.; La Thangue, N. B. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 2009, 15, 57– 66, DOI: 10.1016/j.ccr.2008.12.001[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptVKjsg%253D%253D&md5=bb971959fe4e67320160eb8e925f8945Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosisFotheringham, Susan; Epping, Mirjam T.; Stimson, Lindsay; Khan, Omar; Wood, Victoria; Pezzella, Francesco; Bernards, Rene; La Thangue, Nicholas B.Cancer Cell (2009), 15 (1), 57-66CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.
- 74Mishima, Y.; Santo, L.; Eda, H.; Cirstea, D.; Nemani, N.; Yee, A. J.; O’Donnell, E.; Selig, M. K.; Quayle, S. N.; Arastu-Kapur, S.; Kirk, C.; Boise, L. H.; Jones, S. S.; Raje, N. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br. J. Haematol. 2015, 169, 423– 434, DOI: 10.1111/bjh.13315[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXms1SksLw%253D&md5=3a0757a3514b4db9e3ddb11c6cd0869aRicolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell deathMishima, Yuko; Santo, Loredana; Eda, Homare; Cirstea, Diana; Nemani, Neeharika; Yee, Andrew J.; O'Donnell, Elizabeth; Selig, Martin Karl; Quayle, Steven N.; Arastu-Kapur, Shirin; Kirk, Christopher; Boise, Lawrence H.; Jones, Simon S.; Raje, NoopurBritish Journal of Haematology (2015), 169 (3), 423-434CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We obsd. that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addn. of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumor vol., assocd. with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.
- 75Kawaguchi, Y.; Kovacs, J. J.; McLaurin, A.; Vance, J. M.; Ito, A.; Yao, T. P. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003, 115, 727– 738, DOI: 10.1016/S0092-8674(03)00939-5[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVWgurfL&md5=4bb225e89efa841c73b6ca12284cbb06The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stressKawaguchi, Yoshiharu; Kovacs, Jeffrey J.; McLaurin, Adam; Vance, Jeffery M.; Ito, Akihiro; Yao, Tso-pangCell (Cambridge, MA, United States) (2003), 115 (6), 727-738CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The efficient clearance of cytotoxic misfolded protein aggregates is crit. for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-assocd. deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.
- 76Martínez-Iglesias, O.; Ruiz-Llorente, L.; Sánchez-Martínez, R.; García, L.; Zambrano, A.; Aranda, A. Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin. Transl. Oncol. 2008, 10, 395– 398, DOI: 10.1007/s12094-008-0221-x[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVGlsr3P&md5=50266183f85aae8eae9d1fd6a0113429Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancerMartinez-Iglesias, Olaia; Ruiz-Llorente, Lidia; Sanchez-Martinez, Ruth; Garcia, Laura; Zambrano, Alberto; Aranda, AnaClinical & Translational Oncology (2008), 10 (7), 395-398CODEN: CTOLAM; ISSN:1699-048X. (Springer)A review. Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addn., HDACs can also influence transcription-independent events such as mitosis or DNA (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addn., these compds. inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clin. trials, showing significant anticancer activity both in hematol. and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clin. oncol. market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies.
- 77Thaler, F. Current trends in the development of histone deacetylase inhibitors: a review of recent patent applications. Pharm. Pat. Anal. 2012, 1, 75– 90, DOI: 10.4155/ppa.11.3[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvVaru7c%253D&md5=15fc09940fb573d7461f15b11ca9c2b2Current trends in the development of histone deacetylase inhibitors: a review of recent patent applicationsThaler, FlorianPharmaceutical Patent Analyst (2012), 1 (1), 75-90CODEN: PPAHCN; ISSN:2046-8954. (Future Science Ltd.)A review. Histone deacetylases (HDACs) have become an important target for the treatment of cancer and other diseases. Currently, more than ten HDAC inhibitors have entered clin. studies and two of them have already reached the market. The hydroxamic acid deriv. SAHA (also known as vorinostat or Zolinza) and the cyclic depsipeptide FK228 (romidepsin or Istodax) have gained approval from the US FDA for the treatment of cutaneous T-cell lymphoma. Nevertheless, there has been a continuous effort aimed at discovering a new generation of clin. candidates with improved pharmaceutical properties. This review provides a summary of the most recent patents published from mid-2009 to mid-2011.
- 79Reimer, P. New developments in the treatment of peripheral T-cell lymphoma - role of belinostat. Cancer Manage. Res. 2015, 7, 145– 151, DOI: 10.2147/CMAR.S85351[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbksVSlsw%253D%253D&md5=fb2ce8a29f5403657fa702baca9ef283New developments in the treatment of peripheral T-cell lymphoma - role of BelinostatReimer PeterCancer management and research (2015), 7 (), 145-51 ISSN:1179-1322.Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of rare malignancies that with the exception of anaplastic lymphoma kinase expressing anaplastic large cell lymphoma, share a poor outcome after standard (eg, anthracycline-based) chemotherapy. Most patients are either refractory to initial therapy or eventually relapse. Randomized studies for relapsed/refractory PTCL are not available, however, recently published data show that conventional chemotherapy has very limited efficacy in the salvage setting. Thus, novel drugs are urgently needed to improve the outcome in this setting. Belinostat, a pan-histone deacetylase inhibitor, has demonstrated meaningful efficacy and a favorable toxicity profile in two single-arm Phase II trials on 153 patients with relapsed/refractory PTCL. The conclusive results led to an accelerated approval by the US Food and Drug Administration. The present review summarizes the clinical data available for belinostat, its current role, and future perspectives.
- 80Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.; Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li Shen, Y.; Chen, X. H.; Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.; Justice, R.; Farrell, A. T.; Pazdur, R. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin. Cancer Res. 2015, 21, 2666– 2670, DOI: 10.1158/1078-0432.CCR-14-3119[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVajurfM&md5=c1e64c9d01d18272d25ad03001e7041aFDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell LymphomaLee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.; Ricci, M. Stacey; Saber, Haleh; Habtemariam, Bahru A.; Bullock, Julie; Bloomquist, Erik; Shen, Yuan Li; Chen, Xiao-Hong; Brown, Janice; Mehrotra, Nitin; Dorff, Sarah; Charlab, Rosane; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, RichardClinical Cancer Research (2015), 21 (12), 2666-2670CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered i.v. at a dose of 1000 mg/m2 over 30 min once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiol. readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathol. Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), resp. The median duration of response, the key secondary efficacy endpoint, was 8.4 mo (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. Clin Cancer Res; 21(12); 2666-70. ©2015 AACR.
- 81Poole, R. M. Belinostat: first global approval. Drugs 2014, 74, 1543– 1554, DOI: 10.1007/s40265-014-0275-8[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtl2nsrzL&md5=b8bc6efe62e7fd78d6a9d022a8d96559Belinostat: First Global ApprovalPoole, Raewyn M.Drugs (2014), 74 (13), 1543-1554CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Belinostat [Beleodaq (US)], a small-mol. hydroxamate-type inhibitor of class I, II and IV histone deacetylase (HDAC) enzymes, has been developed by TopoTarget and Spectrum Pharmaceuticals for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat has received its first global approval as monotherapy for this indication in the US, under the Food and Drug Administration's accelerated approval program. This article summarizes the milestones in the development of belinostat leading to this first approval for the treatment of PTCL.
- 82Tandon, N.; Ramakrishnan, V.; Kumar, S. K. Clinical use and applications of histone deacetylase inhibitors in multiple myeloma. Clin. Pharmacol.: Adv. Appl. 2016, 8, 35– 44, DOI: 10.2147/CPAA.S94021[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmtlertro%253D&md5=c5ad697e90297b2a2397737098dde73cClinical use and applications of histone deacetylase inhibitors in multiple myelomaTandon, Nidhi; Ramakrishnan, Vijay; Kumar, Shaji K.Clinical Pharmacology: Advances and Applications (2016), 8 (), 35-44CODEN: CPAAGX; ISSN:1179-1438. (Dove Medical Press Ltd.)The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM. Various preclin. studies helped us to understand the antimyeloma activity of different HDACi in MM as a single agent or in combination with conventional, novel, and immune therapies. The early clin. trials of HDACi depicted only modest single-agent activity, but recent studies have revealed encouraging clin. response rates in combination with other antimyeloma agents, esp. proteasome inhibitors. This led to the approval of the combination of panobinostat and bortezomib for the treatment of relapsed/refractory MM patients with two prior lines of treatment by the US Food and Drug Administration. However, it remains yet to be defined how we can incorporate HDACi in the current therapeutic paradigms for MM that will help to achieve longer disease control and significant survival benefits. In addn., isoform-selective and/or class-selective HDAC inhibition to reduce unfavorable side effects needs further evaluation.
- 83Ribrag, V.; Kim, V. S.; Bouabdallah, R.; Lim, S. T.; Coiffier, B.; Illes, A.; Lemieux, B.; Dyer, M. J. S.; Offner, F.; Felloussi, Z.; Kloos, I.; Luan, Y.; Vezan, R.; Graef, T.; Morschhauser, F. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study. Haematologica 2017, 102, 903– 909, DOI: 10.3324/haematol.2016.154377[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVWlurnP&md5=4368682e077c9e36057685cb45103276Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II studyRibrag, Vincent; Kim, Won Seog; Bouabdallah, Reda; Lim, Soon Thye; Coiffier, Bertrand; Illes, Arpad; Lemieux, Bernard; Dyer, Martin J. S.; Offner, Fritz; Felloussi, Zakia; Kloos, Ioana; Luan, Ying; Vezan, Remus; Graef, Thorsten; Morschhauser, FranckHaematologica (2017), 102 (5), 903-909CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-contg. histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concns. required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between Oct. 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, resp. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses obsd. in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large Bcell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less doseintense week-on-week-off schedule is warranted.
- 84Tak, W. Y.; Ryoo, B. Y.; Lim, H. Y.; Kim, D. Y.; Okusaka, T.; Ikeda, M.; Hidaka, H.; Yeon, J. E.; Mizukoshi, E.; Morimoto, M.; Lee, M. A.; Yasui, K.; Kawaguchi, Y.; Heo, J.; Morita, S.; Kim, T. Y.; Furuse, J.; Katayama, K.; Aramaki, T.; Hara, R.; Kimura, T.; Nakamura, O.; Kudo, M. Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. Invest. New Drugs 2018, 36, 1072– 1084, DOI: 10.1007/s10637-018-0658-x[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs12it7bI&md5=76f6a72614eebfad7cb38e63f0db8f62Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patientsTak, Won Young; Ryoo, Baek-Yeol; Lim, Ho Yeong; Kim, Do-Young; Okusaka, Takuji; Ikeda, Masafumi; Hidaka, Hisashi; Yeon, Jong-Eun; Mizukoshi, Eishiro; Morimoto, Manabu; Lee, Myung-Ah; Yasui, Kohichiroh; Kawaguchi, Yasunori; Heo, Jeong; Morita, Sojiro; Kim, Tae-You; Furuse, Junji; Katayama, Kazuhiro; Aramaki, Takeshi; Hara, Rina; Kimura, Takuya; Nakamura, Osamu; Kudo, MasatoshiInvestigational New Drugs (2018), 36 (6), 1072-1084CODEN: INNDDK; ISSN:0167-6997. (Springer)Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib vs. sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to det. the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was detd. to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 mo with monotherapy vs. 2.8/11.8 mo with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% vs. 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% vs. 2.4%, p < 0.001). Subgroup anal. revealed that median TTP/OS was 1.5/6.9 mo for monotherapy vs. 2.8/13.1 mo for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.
- 85Galli, M.; Salmoiraghi, S.; Golay, J.; Gozzini, A.; Crippa, C.; Pescosta, N.; Rambaldi, A. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann. Hematol. 2010, 89, 185– 190, DOI: 10.1007/s00277-009-0793-8[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt1yltw%253D%253D&md5=0aa6301364211146a0dcb8d97fd38aa8A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myelomaGalli, Monica; Salmoiraghi, Silvia; Golay, Josee; Gozzini, Antonella; Crippa, Claudia; Pescosta, Norbert; Rambaldi, AlessandroAnnals of Hematology (2010), 89 (2), 185-190CODEN: ANHEE8; ISSN:0939-5555. (Springer)ITF2357, an orally effective member of the family of histone deacetylase inhibitors, is a potent inducer of apoptosis and death of multiple myeloma (MM) cells. We performed a phase-II, multiple-dose clin. trial in 19 patients with relapsed or progressive MM to det. the max. tolerated dose (MTD) of ITF2357 administered twice daily for four consecutive days every week for 4 wk (i.e., first cycle). The first six patients received 150 mg ITF2357 twice daily. Since two of them experienced a dose-limiting toxicity (DLT) during the first cycle, the subsequent patients received 100 mg ITF2357 twice daily. This was the MTD, as only one DLT occurred. Up to 12 wk (i.e., three cycles) of treatment were scheduled. Oral dexamethasone was allowed to a max. weekly amt. of 20 mg. Median duration of treatment was 6 wk, ranging from two (two patients) to 12 wk (five patients). Four patients suffered from serious adverse events. Three patients experienced grade 3-4 gastro-intestinal toxicity and three had transient electrocardiog. abnormalities. Thrombocytopenia occurred in all but one patient (grade 3-4 in ten patients). At last follow-up, five patients were in stable disease, five had disease progression, and nine had died all of progressive MM. In conclusion, when given at a dose of 100 mg twice daily alone or combined with dexamethasone, ITF2357 proved tolerable but showed a modest clin. benefit in advanced MM.
- 86Finazzi, G.; Vannucchi, A. M.; Martinelli, V.; Ruggeri, M.; Nobile, F.; Specchia, G.; Pogliani, E. M.; Olimpieri, O. M.; Fioritoni, G.; Musolino, C.; Cilloni, D.; Sivera, P.; Barosi, G.; Finazzi, M. C.; Di Tollo, S.; Demuth, T.; Barbui, T.; Rambaldi, A. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br. J. Haematol. 2013, 161, 688– 694, DOI: 10.1111/bjh.12332[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGisrY%253D&md5=ec3a1a0cd05344cb0975818d459f04d6A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapyFinazzi, Guido; Vannucchi, Alessandro M.; Martinelli, Vincenzo; Ruggeri, Marco; Nobile, Francesco; Specchia, Giorgina; Pogliani, Enrico Maria; Olimpieri, Odoardo Maria; Fioritoni, Giuseppe; Musolino, Caterina; Cilloni, Daniela; Sivera, Piera; Barosi, Giovanni; Finazzi, Maria Chiara; Di Tollo, Silvia; Demuth, Tim; Barbui, Tiziano; Rambaldi, AlessandroBritish Journal of Haematology (2013), 161 (5), 688-694CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythemia vera (PV), unresponsive to the max. tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukemiaNet response criteria were used to assess the primary endpoint after 12 wk of treatment. Complete or partial response was obsd. in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, resp. Control of pruritus was obsd. in 64% and 67% of patients in the 50 and 100 mg groups, resp. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clin. effective in HC-unresponsive PV patients.
- 87Garcia-Manero, G.; Abaza, Y.; Takahashi, K.; Medeiros, B. C.; Arellano, M.; Khaled, S. K.; Patnaik, M.; Odenike, O.; Sayar, H.; Tummala, M.; Patel, P.; Maness-Harris, L.; Stuart, R.; Traer, E.; Karamlou, K.; Yacoub, A.; Ghalie, R.; Giorgino, R.; Atallah, E. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. Blood Adv. 2019, 3, 508– 518, DOI: 10.1182/bloodadvances.2018027409[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslyht7%252FL&md5=4a1a8b98ee7ef7f39ea5e445feb7aa75Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 studyGarcia-Manero, Guillermo; Abaza, Yasmin; Takahashi, Koichi; Medeiros, Bruno C.; Arellano, Martha; Khaled, Samer K.; Patnaik, Mrinal; Odenike, Olatoyosi; Sayar, Hamid; Tummala, Mohan; Patel, Prapti; Maness-Harris, Lori; Stuart, Robert; Traer, Elie; Karamlou, Kasra; Yacoub, Abdulraheem; Ghalie, Richard; Giorgino, Ruben; Atallah, EhabBlood Advances (2019), 3 (4), 508-518CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for std. induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphol. leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapyrelated AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 mo (95% confidence interval [CI], 10-26.5 mo) and 12.6 mo (95% CI, 10-17.7 mo), resp., with a 1-yr OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, resp. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing.
- 88Yalniz, F. F.; Berdeja, J. G.; Maris, M. B.; Lyons, R. M.; Reeves, J. A., Jr; Essell, J. H.; Patel, P.; Sekeres, M.; Hughes, A.; Mappa, S.; Garcia-Manero, G. A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy. Br. J. Haematol. 2020, 188, 404– 412, DOI: 10.1111/bjh.16173[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFOiurk%253D&md5=8e4a85ae70a75b02725bf5cc0d9ea104A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapyYalniz, Fevzi F.; Berdeja, Jesus G.; Maris, Michael B.; Lyons, Roger M.; Reeves, James A., Jr.; Essell, James H.; Patel, Prapti; Sekeres, Mikkael; Hughes, Amanda; Mappa, Silvia; Garcia-Manero, GuillermoBritish Journal of Haematology (2020), 188 (3), 404-412CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Hypomethylating agents (HMAs) are std. of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to est. the clin. improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematol. improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 mo for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
- 89Chu, Q. S.; Nielsen, T. O.; Alcindor, T.; Gupta, A.; Endo, M.; Goytain, A.; Xu, H.; Verma, S.; Tozer, R.; Knowling, M.; Bramwell, V. B.; Powers, J.; Seymour, L. K.; Eisenhauer, E. A. A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200. Ann. Oncol. 2015, 26, 973– 981, DOI: 10.1093/annonc/mdv033[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mrgs1GlsA%253D%253D&md5=911f2bcea1fdcede9dbbcbef8c8e9b21A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†Chu Q S-C; Nielsen T O; Goytain A; Knowling M; Alcindor T; Gupta A; Endo M; Xu H; Powers J; Seymour L K; Eisenhauer E A; Verma S; Tozer R; Bramwell V BAnnals of oncology : official journal of the European Society for Medical Oncology (2015), 26 (5), 973-981 ISSN:.BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.
- 90Child, F.; Ortiz-Romero, P. L.; Alvarez, R.; Bagot, M.; Stadler, R.; Weichenthal, M.; Alves, R.; Quaglino, P.; Beylot-Barry, M.; Cowan, R.; Geskin, L. J.; Pérez-Ferriols, A.; Hellemans, P.; Elsayed, Y.; Phelps, C.; Forslund, A.; Kamida, M.; Zinzani, P. L. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome. Br. J. Dermatol. 2016, 175, 80– 88, DOI: 10.1111/bjd.14427[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1KktbvM&md5=0b64887cee81c36b3667927b3a724ba2Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sezary syndromeChild, F.; Ortiz-Romero, P. L.; Alvarez, R.; Bagot, M.; Stadler, R.; Weichenthal, M.; Alves, R.; Quaglino, P.; Beylot-Barry, M.; Cowan, R.; Geskin, L. J.; Perez-Ferriols, A.; Hellemans, P.; Elsayed, Y.; Phelps, C.; Forslund, A.; Kamida, M.; Zinzani, P. L.British Journal of Dermatology (2016), 175 (1), 80-88CODEN: BJDEAZ; ISSN:0007-0963. (Wiley-Blackwell)Summary : Background : Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. Objectives : To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). Methods : Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. Results : Eight of 26 (25 evaluable) patients achieved ≥ 50% redn. in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 mo. Median PFS was 5·1 mo. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumor biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clin. cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalemia and pyrexia. Conclusions : Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.
- 91Moreau, P.; Facon, T.; Touzeau, C.; Benboubker, L.; Delain, M.; Badamo-Dotzis, J.; Phelps, C.; Doty, C.; Smit, H.; Fourneau, N.; Forslund, A.; Hellemans, P.; Leleu, X. Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma. Leuk. Lymphoma 2016, 57, 1546– 1559, DOI: 10.3109/10428194.2015.1117611[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSitL0%253D&md5=6161989b835b6ebc93b591ed714ed76fQuisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myelomaMoreau, Philippe; Facon, Thierry; Touzeau, Cyrille; Benboubker, Lotfi; Delain, Martine; Badamo-Dotzis, Julie; Phelps, Charles; Doty, Christopher; Smit, Hans; Fourneau, Nele; Forslund, Ann; Hellemans, Peter; Leleu, XavierLeukemia & Lymphoma (2016), 57 (7), 1546-1559CODEN: LELYEA; ISSN:1029-2403. (Taylor & Francis Ltd.)The max. tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/wk) plus s.c. bortezomib (1.3 mg/m2) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was detd. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clin. significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 mo, resp. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone.
- 92Venugopal, B.; Baird, R.; Kristeleit, R. S.; Plummer, R.; Cowan, R.; Stewart, A.; Fourneau, N.; Hellemans, P.; Elsayed, Y.; McClue, S.; Smit, J. W.; Forslund, A.; Phelps, C.; Camm, J.; Evans, T. R.; de Bono, J. S.; Banerji, U. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin. Cancer Res. 2013, 19, 4262– 4272, DOI: 10.1158/1078-0432.CCR-13-0312[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1amt7zP&md5=f4db895a7878fddce61ea9640e427d4dA Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid TumorsVenugopal, Balaji; Baird, Richard; Kristeleit, Rebecca S.; Plummer, Ruth; Cowan, Richard; Stewart, Adam; Fourneau, Nele; Hellemans, Peter; Elsayed, Yusri; McClue, Steve; Smit, Johan W.; Forslund, Ann; Phelps, Charles; Camm, John; Evans, T. R. Jeffry; de Bono, Johann S.; Banerji, UdaiClinical Cancer Research (2013), 19 (15), 4262-4272CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: To det. the max.-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi). Exptl. Design: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titrn. design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clin. efficacy were evaluated at each schedule. Results: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs obsd. were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The max. plasma concn. (Cmax) and area under the plasma concn.-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 mo). Conclusions: The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule. Clin Cancer Res; 19(15); 4262-72. ©2013 AACR.
- 93Yee, A. J.; Bensinger, W. I.; Supko, J. G.; Voorhees, P. M.; Berdeja, J. G.; Richardson, P. G.; Libby, E. N.; Wallace, E. E.; Birrer, N. E.; Burke, J. N.; Tamang, D. L.; Yang, M.; Jones, S. S.; Wheeler, C. A.; Markelewicz, R. J.; Raje, N. S. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016, 17, 1569– 1578, DOI: 10.1016/S1470-2045(16)30375-8[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2isb7J&md5=59fea63c11b7bce7be6bd74f195af04bRicolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trialYee, Andrew J.; Bensinger, William I.; Supko, Jeffrey G.; Voorhees, Peter M.; Berdeja, Jesus G.; Richardson, Paul G.; Libby, Edward N.; Wallace, Ellen E.; Birrer, Nicole E.; Burke, Jill N.; Tamang, David L.; Yang, Min; Jones, Simon S.; Wheeler, Catherine A.; Markelewicz, Robert J.; Raje, Noopur S.Lancet Oncology (2016), 17 (11), 1569-1578CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clin. Motivated by findings from preclin. studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. In this multicenter phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centers in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 wk of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a std. 3 + 3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the max. tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumor activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, no. NCT01583283. Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We obsd. two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A max. tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clin. relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumor activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response. The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma.Acetylon Pharmaceuticals.
- 94Vogl, D. T.; Raje, N.; Jagannath, S.; Richardson, P.; Hari, P.; Orlowski, R.; Supko, J. G.; Tamang, D.; Yang, M.; Jones, S. S.; Wheeler, C.; Markelewicz, R. J.; Lonial, S. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin. Cancer Res. 2017, 23, 3307– 3315, DOI: 10.1158/1078-0432.CCR-16-2526[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFSnurbL&md5=2dd174501d2f331aeb0eff42072001d1Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple MyelomaVogl, Dan T.; Raje, Noopur; Jagannath, Sundar; Richardson, Paul; Hari, Parameswaran; Orlowski, Robert; Supko, Jeffrey G.; Tamang, David; Yang, Min; Jones, Simon S.; Wheeler, Catherine; Markelewicz, Robert J.; Lonial, SagarClinical Cancer Research (2017), 23 (13), 3307-3315CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclin. models suggest that the obsd. synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degrdn. Exptl. Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with std. proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clin. responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematol., gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.
- 95Gao, X.; Shen, L.; Li, X.; Liu, J. Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta-analysis of clinical trials. Exp. Ther. Med. 2019, 18, 1057– 1068, DOI: 10.3892/etm.2019.7704[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFOlu7fF&md5=76b38fadb3a41671d1ac93635c8b3cf7Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta-analysis of clinical trialsGao, Xiao; Shen, Lijing; Li, Xiang; Liu, JiayingExperimental and Therapeutic Medicine (2019), 18 (2), 1057-1068CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)A review. Multiple myeloma (MM) remains incurable primarily due to relapse. Histone deacetylase inhibitors (HDACis) have shown potential application for the treatment of relapsed/refractory multiple myeloma (RRMM). To assess the efficacy and safety of HDACis in RRMM treatment, a systematic review and meta-anal. were conducted based on clin. trial data. A literature search was performed using PubMed, EMBASE, Web of Science and the Cochrane Library databases. Subsequently, 19 trials with 2193 patients treated with one of the three HDACis, panobinostat, ricolinostat and vorinostat, were identified and included in the present study. The efficacy and toxicity of each agent were assessed. The data were pooled using a random effects model in STATA 13.0. The results showed that the overall response rate (ORR) was 0.64 with a 95% confidence interval (CI) of 0.61-0.68 for panobinostat, 0.51 (95% CI, 0.46-0.55) for vorinostat and 0.38 (95% CI, 0.29-0.48) for ricolinostat. Addnl., subgroup anal. revealed an ORR of 0.36 (95% CI, 0.27-0.46) for HDACis-treated bortezomib-refractory MM patients and 0.43 (95% CI, 0.30-0.55) for lenalidomide-refractory patients. The most common grade 3 and 4 hematol. adverse events were thrombocytopenia, neutropenia and anemia. Non-hematol. adverse events included fatigue/asthenia, diarrhea and nausea. In conclusion, anal. of the pooled data revealed that panobinostat-contg. regimens were effective and tolerable for patients with RRMM. Furthermore, lenalidomide-refractory patients may derive greater benefits from these regimens. More clin. and real-world studies are required to validate these results.
- 96Shimizu, T.; LoRusso, P. M.; Papadopoulos, K. P.; Patnaik, A.; Beeram, M.; Smith, L. S.; Rasco, D. W.; Mays, T. A.; Chambers, G.; Ma, A.; Wang, J.; Laliberte, R.; Voi, M.; Tolcher, A. W. Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors. Clin. Cancer Res. 2014, 20, 5032– 5040, DOI: 10.1158/1078-0432.CCR-14-0570[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12gtbzP&md5=62860afa08733980f47047880e11a5baPhase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid TumorsShimizu, Toshio; LoRusso, Patricia M.; Papadopoulos, Kyri P.; Patnaik, Amita; Beeram, Muralidhar; Smith, Lon S.; Rasco, Drew W.; Mays, Theresa A.; Chambers, Glenda; Ma, Anna; Wang, Jing; Laliberte, Robert; Voi, Maurizio; Tolcher, Anthony W.Clinical Cancer Research (2014), 20 (19), 5032-5040CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-h i.v. (i.v.) infusion for 5 consecutive days every 2 wk. Exptl. Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m2/day) following a std. 3 + 3 dose escalation design. Results: The MTD was detd. to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean max. concn. (Cmax), clearance (CL), vol. of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 h, resp. Acetylated histone H3 induction was obsd. in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. Conclusion: CUDC-101 administered by 1-h i.v. infusion for 5 consecutive days every 2 wk was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clin. testing. Clin Cancer Res; 20(19); 5032-40. ©2014 AACR.
- 97Galloway, T. J.; Wirth, L. J.; Colevas, A. D.; Gilbert, J.; Bauman, J. E.; Saba, N. F.; Raben, D.; Mehra, R.; Ma, A. W.; Atoyan, R.; Wang, J.; Burtness, B.; Jimeno, A. A phase I study of CUDC-101, a multitarget inhibitor of hdacs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 2015, 21, 1566– 1573, DOI: 10.1158/1078-0432.CCR-14-2820[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtVahs7o%253D&md5=dd6b5663ffbf995b5def843a8b8b7556A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell CarcinomaGalloway, Thomas J.; Wirth, Lori J.; Colevas, Alexander D.; Gilbert, Jill; Bauman, Julie E.; Saba, Nabil F.; Raben, David; Mehra, Ranee; Ma, Anna W.; Atoyan, Ruzanna; Wang, Jing; Burtness, Barbara; Jimeno, AntonioClinical Cancer Research (2015), 21 (7), 1566-1573CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)CUDC-101 is a small mol. that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclin. activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to det. the max. tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC. CUDC-101 monotherapy was administered i.v. three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 wk) and external beam radiation (70 Gy to gross disease) over 7 wk. Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-neg. The MTD of CUDC-101-based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression. CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566-73. ©2015 AACR.
- 98Shi, Y.; Jia, B.; Xu, W.; Li, W.; Liu, T.; Liu, P.; Zhao, W.; Zhang, H.; Sun, X.; Yang, H.; Zhang, X.; Jin, J.; Jin, Z.; Li, Z.; Qiu, L.; Dong, M.; Huang, X.; Luo, Y.; Wang, X.; Wang, X.; Wu, J.; Xu, J.; Yi, P.; Zhou, J.; He, H.; Liu, L.; Shen, J.; Tang, X.; Wang, J.; Yang, J.; Zeng, Q.; Zhang, Z.; Cai, Z.; Chen, X.; Ding, K.; Hou, M.; Huang, H.; Li, X.; Liang, R.; Liu, Q.; Song, Y.; Su, H.; Gao, Y.; Liu, L.; Luo, J.; Su, L.; Sun, Z.; Tan, H.; Wang, H.; Wang, J.; Wang, S.; Zhang, H.; Zhang, X.; Zhou, D.; Bai, O.; Wu, G.; Zhang, L.; Zhang, Y. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J. Hematol. Oncol. 2017, 10, 69, DOI: 10.1186/s13045-017-0439-6[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXksl2htrk%253D&md5=6b3172600b76e6025fc5569446f6362dChidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in ChinaShi, Yuankai; Jia, Bo; Xu, Wei; Li, Wenyu; Liu, Ting; Liu, Peng; Zhao, Weili; Zhang, Huilai; Sun, Xiuhua; Yang, Haiyan; Zhang, Xi; Jin, Jie; Jin, Zhengming; Li, Zhiming; Qiu, Lugui; Dong, Mei; Huang, Xiaobing; Luo, Yi; Wang, Xiaodong; Wang, Xin; Wu, Jianqiu; Xu, Jingyan; Yi, Pingyong; Zhou, Jianfeng; He, Hongming; Liu, Lin; Shen, Jianzhen; Tang, Xiaoqiong; Wang, Jinghua; Yang, Jianmin; Zeng, Qingshu; Zhang, Zhihui; Cai, Zhen; Chen, Xiequn; Ding, Kaiyang; Hou, Ming; Huang, Huiqiang; Li, Xiaoling; Liang, Rong; Liu, Qifa; Song, Yuqin; Su, Hang; Gao, Yuhuan; Liu, Lihong; Luo, Jianmin; Su, Liping; Sun, Zimin; Tan, Huo; Wang, Huaqing; Wang, Jingwen; Wang, Shuye; Zhang, Hongyu; Zhang, Xiaohong; Zhou, Daobin; Bai, Ou; Wu, Gang; Zhang, Liling; Zhang, YizhuoJournal of Hematology & Oncology (2017), 10 (), 69/1-69/5CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clin. trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from Apr. 2015 to Feb. 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, resp. The ORR and DCR were 51.18 and 74.02%, resp., for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.
- 99Lu, X.; Ning, Z.; Li, Z.; Cao, H.; Wang, X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis. Res. 2016, 5, 185– 191, DOI: 10.5582/irdr.2016.01024[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svkt1Cnsg%253D%253D&md5=5c1f310ea15bb4a706f54d5fdc55c7d5Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in ChinaLu Xianping; Ning Zhiqiang; Li Zhibin; Cao Haixiang; Wang XinhaoIntractable & rare diseases research (2016), 5 (3), 185-91 ISSN:2186-3644.Peripheral T-cell lymphoma (PTCL) is a set of rare and highly heterogeneous group of mature T- and NK-cell neoplasms associated with poor outcomes and lack of standard and effective therapies. The total number of newly diagnosed cases of PTCL yearly in China is estimated about 50,000. Chidamide (CS055) is a novel and orally active benzamide class of histone deacetylase (HDAC) inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, the enzymes that are involved and play an important role in tumor initiation and development in both tumor cells and their surrounding micro-environment. Functioning as a genuine epigenetic modulator, chidamide induces growth arrest and apoptosis in tumor cells and enhances cellular antitumor immunity. Based on the overall results from preclinical and phase I clinical studies, exploratory and pivotal phase II trials of chidamide for relapsed or refractory PTCL were conducted from March 2009 to May 2012, and the results led to CFDA approval of chidamide for the indication in December 2014, being the first approved orphan drug according to the research & development approach of orphan drugs in China, as well as the first orally active drug for PTCL in China and worldwide.
- 100Richards, D. A.; Boehm, K. A.; Waterhouse, D. M.; Wagener, D. J.; Krishnamurthi, S. S.; Rosemurgy, A.; Grove, W.; Macdonald, K.; Gulyas, S.; Clark, M.; Dasse, K. D. Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study. Ann. Oncol. 2006, 17, 1096– 1102, DOI: 10.1093/annonc/mdl081[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zotVakug%253D%253D&md5=d1c9da13030a47407ffc93a2fdf8a5fdGemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter studyRichards D A; Boehm K A; Waterhouse D M; Wagener D J; Krishnamurthi S S; Rosemurgy A; Grove W; Macdonald K; Gulyas S; Clark M; Dasse K DAnnals of oncology : official journal of the European Society for Medical Oncology (2006), 17 (7), 1096-102 ISSN:0923-7534.BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.
- 101Hauschild, A.; Trefzer, U.; Garbe, C.; Kaehler, K. C.; Ugurel, S.; Kiecker, F.; Eigentler, T.; Krissel, H.; Schott, A.; Schadendorf, D. Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. Melanoma Res. 2008, 18, 274– 278, DOI: 10.1097/CMR.0b013e328307c248[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFWnur8%253D&md5=bcbe4c6a1d13dfbc1e93315b703f982fMulticenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanomaHauschild, Axel; Trefzer, Uwe; Garbe, Claus; Kaehler, Katharina C.; Ugurel, Selma; Kiecker, Felix; Eigentler, Thomas; Krissel, Heiko; Schott, Astrid; Schadendorf, DirkMelanoma Research (2008), 18 (4), 274-278CODEN: MREEEH; ISSN:0960-8931. (Lippincott Williams & Wilkins)Systemic treatment of metastatic melanoma is of low efficacy, and new therapeutic strategies are needed. Histone deacetylase inhibitors are supposed to restore the expression of tumor suppressor genes and induce tumor cell differentiation, growth arrest, and apoptosis. This study was aimed to evaluate the efficacy, safety, and pharmacokinetics of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) in patients with pretreated metastatic melanoma. Patients with unresectable AJCC stage IV melanoma refractory to at least one earlier systemic therapy were randomized to receive MS-275 3 mg biweekly (days 1+15, arm A) or 7 mg weekly (days 1+8+15, arm B), in 4-wk cycles. The primary study endpoint was objective tumor response, secondary endpoints were safety and time-to-progression. On the basis of Simon's two-stage design, the study initially allowed an entry of 14 patients per arm; if there was at least one responder, addnl. 33 patients were to be enrolled. Among 28 patients enrolled, no objective response was detected. Four (29%) patients in arm A and three (21%) patients in arm B showed disease stabilizations. Median time-to-progression was comparable in both arms with 55.5 vs. 51.5 days, resp.; median overall survival was 8.84 mo. Toxicity was mild to moderate with nausea (39%) and hypophosphatemia (29%) as the most frequently reported events. No treatment-related serious adverse events occurred. Single-agent treatment with MS-275 was well-tolerated and showed long-term tumor stabilizations, but no objective responses in pretreated metastatic melanoma. Further evaluation of MS-275 in combination schedules is warranted.
- 102Batlevi, C. L.; Kasamon, Y.; Bociek, R. G.; Lee, P.; Gore, L.; Copeland, A.; Sorensen, R.; Ordentlich, P.; Cruickshank, S.; Kunkel, L.; Buglio, D.; Hernandez-Ilizaliturri, F.; Younes, A. ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica 2016, 101, 968– 975, DOI: 10.3324/haematol.2016.142406[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aqsrnK&md5=ff56afc5c31a8693aa42eccb400cfef6ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphomaBatlevi, Connie Lee; Kasamon, Yvette; Bociek, R. Gregory; Lee, Peter; Gore, Lia; Copeland, Amanda; Sorensen, Rachel; Ordentlich, Peter; Cruickshank, Scott; Kunkel, Lori; Buglio, Daniela; Hernandez-Ilizaliturri, Francisco; Younes, AnasHaematologica (2016), 101 (8), 968-975CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 wk). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat anal., the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 mo) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor redn. was obsd. in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 mo, resp. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose redns. or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies.
- 103Pili, R.; Quinn, D. I.; Hammers, H. J.; Monk, P.; George, S.; Dorff, T. B.; Olencki, T.; Shen, L.; Orillion, A.; Lamonica, D.; Fragomeni, R. S.; Szabo, Z.; Hutson, A.; Groman, A.; Perkins, S. M.; Piekarz, R.; Carducci, M. A. Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2: A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870). Clin. Cancer Res. 2017, 23, 7199– 7208, DOI: 10.1158/1078-0432.CCR-17-1178[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWht7zN&md5=c8e1ddb8639f4b3b57ccc239eafd4b30Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)Pili, Roberto; Quinn, David I.; Hammers, Hans J.; Monk, Paul; George, Saby; Dorff, Tanya B.; Olencki, Thomas; Shen, Li; Orillion, Ashley; Lamonica, Dominick; Fragomeni, Roberto S.; Szabo, Zsolt; Hutson, Alan; Groman, Adrienne; Perkins, Susan M.; Piekarz, Richard; Carducci, Michael A.Clinical Cancer Research (2017), 23 (23), 7199-7208CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: On the basis of preclin. data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clin. study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Exptl. Design: Clear cell histol., no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed std. dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival. Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 mo, the objective response rate was 37% [95% confidence interval (CI), 22%-53%], the median progression-free survival was 13.8 mo (95% CI, 6.0-18.8), and the median overall survival was 65.3 mo (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were obsd. following treatment with entinostat, and lower nos. were assocd. with response (P = 0.03). Conclusions: This trial suggests a promising clin. activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199-208. ©2017 AACR.
- 104Younes, A.; Oki, Y.; Bociek, R. G.; Kuruvilla, J.; Fanale, M.; Neelapu, S.; Copeland, A.; Buglio, D.; Galal, A.; Besterman, J.; Li, Z.; Drouin, M.; Patterson, T.; Ward, M. R.; Paulus, J. K.; Ji, Y.; Medeiros, L. J.; Martell, R. E. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011, 12, 1222– 1228, DOI: 10.1016/S1470-2045(11)70265-0[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFGjt77O&md5=c6f7748fe47bad8522fb16ef67195231Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trialYounes, Anas; Oki, Yasuhiro; Bociek, R. Gregory; Kuruvilla, John; Fanale, Michelle; Neelapu, Sattva; Copeland, Amanda; Buglio, Daniela; Galal, Ahmed; Besterman, Jeffrey; Li, Zuomei; Drouin, Michel; Patterson, Tracy; Ward, M. Renee; Paulus, Jessica K.; Ji, Yuan; Medeiros, L. Jeffrey; Martell, Robert E.Lancet Oncology (2011), 12 (13), 1222-1228CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Summary: Background: The prognosis of patients with relapsed Hodgkin's lymphoma, esp. those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods: Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per wk, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analyzed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, no. NCT00358982. Findings: 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose redns. were necessary in the 110 mg cohort, we treated 28 addnl. patients with a dose of 85 mg. On the basis of intent-to-treat anal., the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation: Mocetinostat, 85 mg three times per wk, has promising single-agent clin. activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding: MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
- 105Batlevi, C. L.; Crump, M.; Andreadis, C.; Rizzieri, D.; Assouline, S. E.; Fox, S.; van der Jagt, R. H. C.; Copeland, A.; Potvin, D.; Chao, R.; Younes, A. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br. J. Haematol. 2017, 178, 434– 441, DOI: 10.1111/bjh.14698[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1SmsLbP&md5=eafed027b27b4e9eb1b2226c8eb88aabA phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphomaBatlevi, Connie L.; Crump, Michael; Andreadis, Charalambos; Rizzieri, David; Assouline, Sarit E.; Fox, Susan; van der Jagt, Richard H. C.; Copeland, Amanda; Potvin, Diane; Chao, Richard; Younes, AnasBritish Journal of Haematology (2017), 178 (3), 434-441CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary: Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-wk cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clin. benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, resp. Progression-free survival ranged from 1·8 to 22·8 mo and 11·8 to 26·3 mo in responders with DLBCL and FL, resp. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clin. benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.
- 106Tresckow, B.; Sayehli, C.; Aulitzky, W. E.; Goebeler, M. E.; Schwab, M.; Braz, E.; Krauss, B.; Krauss, R.; Hermann, F.; Bartz, R.; Engert, A. Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies. Eur. J. Haematol. 2019, 102, 163– 173, DOI: 10.1111/ejh.13188
- 107Shimony, S.; Horowitz, N.; Ribakovsky, E.; Rozovski, U.; Avigdor, A.; Zloto, K.; Berger, T.; Avivi, I.; Perry, C.; Abadi, U.; Raanani, P.; Gafter-Gvili, A.; Gurion, R. Romidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma: Real-life data from a national multicenter observational study. Hematol. Oncol. 2019, 37, 569– 577, DOI: 10.1002/hon.2691[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFGmtw%253D%253D&md5=fcace7d754fb4c564b95a82b702eae6bRomidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma: Real-life data from a national multicenter observational studyShimony, Shai; Horowitz, Netanel; Ribakovsky, Elena; Rozovski, Uri; Avigdor, Abraham; Zloto, Keren; Berger, Tamar; Avivi, Irit; Perry, Chava; Abadi, Uri; Raanani, Pia; Gafter-Gvili, Anat; Gurion, RonitHematological Oncology (2019), 37 (5), 569-577CODEN: HAONDL; ISSN:0278-0232. (Wiley-Blackwell)Currently, there is paucity of real-life data on efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival, event-free survival, overall response rate, complete response and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 mo, EFS was 1.9 mo, ORR rate was 33%, and 12.5% achieved CR. In a univariate anal., predictors for longer EFS include any response to therapy, no. of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate anal. for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematol. Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of pivotal phase II trials. PTCL subtype and the no. of previous lines of therapy have impact on EFS. In addn., patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.
- 108Atadja, P. Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges. Cancer Lett. 2009, 280, 233– 241, DOI: 10.1016/j.canlet.2009.02.019[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsF2jtL4%253D&md5=4c487a2f8dc13f72cecf105d9fae97d9Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challengesAtadja, PeterCancer Letters (Shannon, Ireland) (2009), 280 (2), 233-241CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Ireland Ltd.)A review. The histone deacetylase (HDAC) inhibitors are emerging as a highly useful class of anticancer agents that inhibit the enzyme HDAC involved in the deacetylation of histone and non-histone cellular proteins. The HDAC inhibitor, panobinostat (LBH589, Novartis Pharmaceuticals), achieves potent inhibition of all HDAC enzymes implicated in cancer and has demonstrated potent anti-tumor activity in preclin. models and promising clin. efficacy in cancer patients. In this review we discuss the successes and challenges surrounding the development of panobinostat, focusing on its proposed mechanism of action, preclin. anti-tumor activity, and early clin. efficacy in hematol. and solid tumors.
- 109Wang, Y.; Stowe, R. L.; Pinello, C. E.; Tian, G.; Madoux, F.; Li, D.; Zhao, L. Y.; Li, J. L.; Wang, Y.; Wang, Y.; Ma, H.; Hodder, P.; Roush, W. R.; Liao, D. Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases. Chem. Biol. 2015, 22, 273– 284, DOI: 10.1016/j.chembiol.2014.12.015[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtlWjsrg%253D&md5=b4e40e24ebe7e1ee7f6f1dacefaa5a39Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone DeacetylasesWang, Yunfei; Stowe, Ryan L.; Pinello, Christie E.; Tian, Guimei; Madoux, Franck; Li, Dawei; Zhao, Lisa Y.; Li, Jian-Liang; Wang, Yuren; Wang, Yuan; Ma, Haiching; Hodder, Peter; Roush, William R.; Liao, DaiqingChemistry & Biology (Oxford, United Kingdom) (2015), 22 (2), 273-284CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clin. anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compds. are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compd., UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biol. activities in suppressing tumor cell proliferation support further preclin. development of the UF010 class of compds. for potential therapeutic applications.
- 110Ho, T. C. S.; Chan, A. H. Y.; Ganesan, A. Thirty years of hdac inhibitors: 2020 insight and hindsight. J. Med. Chem. 2020, 63, 12460– 12484, DOI: 10.1021/acs.jmedchem.0c00830[ACS Full Text
], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlSisrzP&md5=1deb2ad5787797a9ee98dcf7bdade52cThirty Years of HDAC Inhibitors: 2020 Insight and HindsightHo, Terence C. S.; Chan, Alex H. Y.; Ganesan, A.Journal of Medicinal Chemistry (2020), 63 (21), 12460-12484CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clin. development for oncol. as well as other therapeutic indications. This Perspective reviews the biol. and medicinal chem. advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms. - 111Mandl-Weber, S.; Meinel, F. G.; Jankowsky, R.; Oduncu, F.; Schmidmaier, R.; Baumann, P. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol. 2010, 149, 518– 528, DOI: 10.1111/j.1365-2141.2010.08124.x[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXns1eqt70%253D&md5=16b57835f5e5d19d8cd587b299820d98The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cellsMandl-Weber, Sonja; Meinel, Felix G.; Jankowsky, Ruediger; Oduncu, Fuat; Schmidmaier, Ralf; Baumann, PhilippBritish Journal of Haematology (2010), 149 (4), 518-528CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Inhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti-myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro. Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concn. (IC50) = 43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concns. of resminostat abrogated cell growth and strongly induced apoptosis (IC50 = 2·5-3 μmol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 μmol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were obsd. for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S-2209. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor.
- 112Novotny-Diermayr, V.; Sangthongpitag, K.; Hu, C. Y.; Wu, X.; Sausgruber, N.; Yeo, P.; Greicius, G.; Pettersson, S.; Liang, A. L.; Loh, Y. K.; Bonday, Z.; Goh, K. C.; Hentze, H.; Hart, S.; Wang, H.; Ethirajulu, K.; Wood, J. M. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol. Cancer Ther. 2010, 9, 642– 652, DOI: 10.1158/1535-7163.MCT-09-0689[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivFens7Y%253D&md5=ffe0b917c40862c4ca0b414c8ef4c493SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal CancerNovotny-Diermayr, Veronica; Sangthongpitag, Kanda; Hu, Chang Yong; Wu, Xiaofeng; Sausgruber, Nina; Yeo, Pauline; Greicius, Gediminas; Pettersson, Sven; Liang, Ai Leng; Loh, Yung Kiang; Bonday, Zahid; Goh, Kee Chuan; Hentze, Hannes; Hart, Stefan; Wang, Haishan; Ethirajulu, Kantharaj; Wood, Jeanette MarjorieMolecular Cancer Therapeutics (2010), 9 (3), 642-652CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Although clin. responses in liq. tumors and certain lymphomas have been reported, the clin. efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concns. of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochem., pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% vs. 48% for SAHA (both at max. tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APCmin mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clin. data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacol. advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. Mol Cancer Ther; 9(3); 642-52.
- 113Cai, X.; Zhai, H. X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C. J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem. 2010, 53, 2000– 2009, DOI: 10.1021/jm901453q[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslSgsb0%253D&md5=d4dc339f2fd750d52e511abf3dbf18bdDiscovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of CancerCai, Xiong; Zhai, Hai-Xiao; Wang, Jing; Forrester, Jeffrey; Qu, Hui; Yin, Ling; Lai, Cheng-Jung; Bao, Rudi; Qian, ChanggengJournal of Medicinal Chemistry (2010), 53 (5), 2000-2009CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compds. with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clin. development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, resp. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compd. that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
- 114Ning, Z. Q.; Li, Z. B.; Newman, M. J.; Shan, S.; Wang, X. H.; Pan, D. S.; Zhang, J.; Dong, M.; Du, X.; Lu, X. P. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother. Pharmacol. 2012, 69, 901– 909, DOI: 10.1007/s00280-011-1766-x[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvVCrsr4%253D&md5=a0055f5a84ad0a9d8d1bd907339cab0fChidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicityNing, Zhi-Qiang; Li, Zhi-Bin; Newman, Michael J.; Shan, Song; Wang, Xin-Hao; Pan, De-Si; Zhang, Jin; Dong, Mei; Du, Xin; Lu, Xian-PingCancer Chemotherapy and Pharmacology (2012), 69 (4), 901-909CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose. Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor of the benzamide class currently under clin. development in cancer indications. This study reports the in vitro and in vivo antitumor characteristics of the compd. Methods. Selectivity and potency of chidamide in inhibition of HDAC isotypes were analyzed by using a panel of human recombinant HDAC proteins. Tumor cell lines either in culture or inoculated in nude mice were used for the evaluation of the compd.'s antitumor activity. To investigate the immune cell-mediated antitumor effect, isolated peripheral blood mononuclear cells from healthy donors were treated with chidamide, and cytotoxicity and expression of relevant surface proteins were analyzed. Microarray gene expression studies were performed on peripheral white blood cells from two T-cell lymphoma patients treated with chidamide. Results. Chidamide was found to be a low nanomolar inhibitor of HDAC1, 2, 3, and 10, the HDAC isotypes well documented to be assocd. with the malignant phenotype. Significant and broad spectrum in vitro and in vivo antitumor activity, including a wide therapeutic index, was obsd. Chidamide was also shown to enhance the cytotoxic effect of human peripheral mononuclear cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in NK cell functions. Furthermore, the expression of a no. of genes involved in immune cell-mediated antitumor activity was obsd. to be upregulated in peripheral white blood cells from two T-cell lymphoma patients who responded to chidamide administration. Conclusions. The results presented in this study provide evidence that chidamide has potential applicability for the treatment of a variety of tumor types, either as a single agent or in combination therapies.
- 115Fournel, M.; Bonfils, C.; Hou, Y.; Yan, P. T.; Trachy-Bourget, M. C.; Kalita, A.; Liu, J.; Lu, A. H.; Zhou, N. Z.; Robert, M. F.; Gillespie, J.; Wang, J. J.; Ste-Croix, H.; Rahil, J.; Lefebvre, S.; Moradei, O.; Delorme, D.; Macleod, A. R.; Besterman, J. M.; Li, Z. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 2008, 7, 759– 768, DOI: 10.1158/1535-7163.MCT-07-2026[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Gms70%253D&md5=48604f141d969585efaa71c4005496cfMGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivoFournel, Marielle; Bonfils, Claire; Hou, Yu; Yan, Pu Theresa; Trachy-Bourget, Marie-Claude; Kalita, Ann; Liu, Jianhong; Lu, Ai-Hua; Zhou, Nancy Z.; Robert, Marie-France; Gillespie, Jeffrey; Wang, James J.; Ste-Croix, Helene; Rahil, Jubrail; Lefebvre, Sylvain; Moradei, Oscar; Delorme, Daniel; MacLeod, A. Robert; Besterman, Jeffrey M.; Li, ZuomeiMolecular Cancer Therapeutics (2008), 7 (4), 759-768CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clin. investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clin. investigation is warranted. [Mol Cancer Ther 2008;7(4):759-68].
- 116Pinkerneil, M.; Hoffmann, M. J.; Kohlhof, H.; Schulz, W. A.; Niegisch, G. Evaluation of the therapeutic potential of the novel isotype specific HDAC inhibitor 4SC-202 in urothelial carcinoma cell lines. Target Oncol. 2016, 11, 783– 798, DOI: 10.1007/s11523-016-0444-7[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FlslWjsQ%253D%253D&md5=8decc6b1e3ff3d96fc12e0661246fe7cEvaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell LinesPinkerneil Maria; Hoffmann Michele J; Schulz Wolfgang A; Niegisch Gunter; Kohlhof HellaTargeted oncology (2016), 11 (6), 783-798 ISSN:.BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models. AIM: The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines. METHODS: We determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control. RESULTS: 4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15-0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment. CONCLUSION: Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC.
- 117Subramanian, S.; Bates, S. E.; Wright, J. J.; Espinoza-Delgado, I.; Piekarz, R. L. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals 2010, 3, 2751– 2767, DOI: 10.3390/ph3092751[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFSmtrvK&md5=d0937756ff0e5582c1e33901c913ff97Clinical toxicities of histone deacetylase inhibitorsSubramanian, Srividya; Bates, Susan E.; Wright, John J.; Espinoza-Delgado, Igor; Piekarz, Richard L.Pharmaceuticals (2010), 3 (), 2751-2767CODEN: PHARH2; ISSN:1424-8247. (Molecular Diversity Preservation International)A review. The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chem. compds. from unrelated chem. classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the obsd. toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addn., since preclin. models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities obsd. in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clin. experience is needed to det. the relative frequency of the obsd. side effects, and to identify and develop approaches to mitigate potential clin. sequelae.
- 118Tan, J.; Cang, S.; Ma, Y.; Petrillo, R. L.; Liu, D. Novel histone deacetylase inhibitors inclinical trials as anti-cancer agents. J. Hematol. Oncol. 2010, 3, 5, DOI: 10.1186/1756-8722-3-5[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7jtFejtg%253D%253D&md5=399a6c058fd597450221aff2648d8c0fNovel histone deacetylase inhibitors in clinical trials as anti-cancer agentsTan Jiahuai; Cang Shundong; Ma Yuehua; Petrillo Richard L; Liu DelongJournal of hematology & oncology (2010), 3 (), 5 ISSN:.Histone deacetylases (HDACs) can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of HDACs. One of the HDAC inhibitors, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma (CTCL) for patients with progressive, persistent, or recurrent disease on or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumor drugs in CTCL and other malignancies. At least 80 clinical trials are underway, testing more than eleven different HDAC inhibitory agents including both hematological and solid malignancies. This review focuses on recent development in clinical trials testing HDAC inhibitors as anti-tumor agents.
- 119Taunton, J.; Hassig, C. A.; Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 1996, 272, 408– 411, DOI: 10.1126/science.272.5260.408[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVegsr8%253D&md5=fda244b40a10d5bc75f94fcc6fae189fA mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3pTaunton, Jack; Hassig, Christian A.; Schreiber, Stuart L.Science (Washington, D. C.) (1996), 272 (5260), 408-11CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a human Jurkat T cell library. As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p, these results support a role for histone deacetylase as a key regulator of eukaryotic transcription.
- 120Yang, W. M.; Inouye, C.; Zeng, Y.; Bearss, D.; Seto, E. Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 12845– 12850, DOI: 10.1073/pnas.93.23.12845[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmvV2lsLg%253D&md5=764b34dc10cc26e04cd7460b6149ebc3Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3Yang, Wen-Ming; Inouye, Carla; Zeng, Yingying; Bearss, David; Seto, EdwardProceedings of the National Academy of Sciences of the United States of America (1996), 93 (23), 12845-12850CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)YY1 is a mammalian zinc-finger transcription factor with unusual structural and functional features. It has been implicated as a pos. and a neg. regulatory factor that binds to the CCATNTT consensus DNA element located in promoters of many cellular and viral genes. A mammalian cDNA that encodes a YY1-binding protein and possesses sequence homol. with the yeast transcriptional factor RPD3 was identified. A Gal4 DNA binding domain-mammalian RPD3 fusion protein strongly represses transcriptional from a promoter contg. Gal4 binding sites. Assocn. between YY1 and mammalian RPD3 requires a glycine-rich region on YY1. Mutations in this region abolish the interaction with mammalian RPD3 and eliminate transcriptional repression by YY1. These data suggest that YY1 neg. regulates transcription by tethering RPD3 to DNA as a cofactor and that this transcriptional mechanism is highly conserved from yeast to human.
- 121Yang, W. M.; Yao, Y. L.; Sun, J. M.; Davie, J. R.; Seto, E. Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J. Biol. Chem. 1997, 272, 28001– 28007, DOI: 10.1074/jbc.272.44.28001[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt12lt7s%253D&md5=cf9e3e377ef706b4a49043d54c1ef11aIsolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene familyYang, Wen-Ming; Yao, Ya-Li; Sun, Jian-Min; Davie, James R.; Seto, EdwardJournal of Biological Chemistry (1997), 272 (44), 28001-28007CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Several human cDNAs encoding a histone deacetylase protein, HDAC3, have been isolated. Anal. of the predicted amino acid sequence of HDAC3 revealed an open reading frame of 428 amino acids with a predicted mol. mass of 49 kDa. The HDAC3 protein is 50% identical in DNA sequence and 53% identical in protein sequence compared with the previously cloned human HDAC1. Comparison of the HDAC3 sequence with human HDAC2 also yielded similar results, with 51% identity in DNA sequence and 52% identity in protein sequence. The expressed HDAC3 protein is functionally active because it possesses histone deacetylase activity, represses transcription when tethered to a promoter, and binds transcription factor YY1. Similar to HDAC1 and HDAC2, HDAC3 is ubiquitously expressed in many different cell types.
- 122Thomas, E. A. Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders; Therapeutic implications for selective HDAC1/HDAC3 inhibitors. Pharmaceuticals 2014, 7, 634– 661, DOI: 10.3390/ph7060634[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1CqtrbI&md5=44797d30e06e109682073a9ec7008c50Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders: therapeutic implications for selective HDAC1/HDAC3 inhibitorsThomas, Elizabeth A.Pharmaceuticals (2014), 7 (6), 634-661, 28CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various exptl. models of neurol. disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biol. roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington's disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclin. efficacy of these compds. remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.
- 123Broide, R. S.; Redwine, J. M.; Aftahi, N.; Young, W.; Bloom, F. E.; Winrow, C. J. Distribution of histone deacetylases 1–11 in the rat brain. J. Mol. Neurosci. 2007, 31, 47– 58, DOI: 10.1007/BF02686117[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXls1GqtL8%253D&md5=8b0ef986705015f17dee856b602a99eaDistribution of histone deacetylases 1-11 in the rat brainBroide, Ron S.; Redwine, Jeff M.; Aftahi, Najla; Young, Warren; Bloom, Floyd E.; Winrow, Christopher J.Journal of Molecular Neuroscience (2007), 31 (1), 47-58CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling mols. is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyltransferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurodegeneration. The authors initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resoln. in situ hybridization (ISH) and imaging technol. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addn., immunohistochem. was performed on these samples to sep. examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled stds. and thereby enabled semiquant. anal. of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examg. the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
- 124Karagianni, P.; Wong, J. HDAC3: taking the SMRT-N-CoRrect road to repression. Oncogene 2007, 26, 5439– 5449, DOI: 10.1038/sj.onc.1210612[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXovFersr4%253D&md5=9632389f7a794442f529b1f71fad8053HDAC3: taking the SMRT-N-CoRrect road to repressionKaragianni, P.; Wong, J.Oncogene (2007), 26 (37), 5439-5449CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the compn., regulation and mechanism of action of the SMRT/N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiol. processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation.
- 125Guenther, M. G.; Barak, O.; Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 2001, 21, 6091– 6101, DOI: 10.1128/MCB.21.18.6091-6101.2001[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmsFKmtr0%253D&md5=08a7ef9200c66413a373923873b3442cThe SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3Guenther, Matthew G.; Barak, Orr; Lazar, Mitchell A.Molecular and Cellular Biology (2001), 21 (18), 6091-6101CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.
- 126Ishizuka, T.; Lazar, M. A. The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol. Cell. Biol. 2003, 23, 5122– 5131, DOI: 10.1128/MCB.23.15.5122-5131.2003[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlslGnurk%253D&md5=e6374d9cad91e51082a596ab7afe69d9The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptorIshizuka, Takahiro; Lazar, Mitchell A.Molecular and Cellular Biology (2003), 23 (15), 5122-5131CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is assocd. with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is crit. for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.
- 127Yu, J.; Li, Y.; Ishizuka, T.; Guenther, M. G.; Lazar, M. A. A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J. 2003, 22, 3403– 3410, DOI: 10.1093/emboj/cdg326[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltFyhtLc%253D&md5=92b529e9ba046eabbd075830e394b1d9A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylationYu, Jiujiu; Li, Yun; Ishizuka, Takahiro; Guenther, Matthew G.; Lazar, Mitchell A.EMBO Journal (2003), 22 (13), 3403-3410CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Nuclear receptor corepressors SMRT (silencing mediator of retinoid and thyroid receptors) and N-CoR (nuclear receptor corepressor) recruit histone deacetylase (HDAC) activity to targeted regions of chromatin. These corepressors contain a closely spaced pair of SANT motifs whose sequence and organization is highly conserved. The N-terminal SANT is a crit. component of a deacetylase activation domain (DAD) that binds and activates HDAC3. Here, we show that the second SANT motif functions as part of a histone interaction domain (HID). The HID enhances repression by increasing the affinity of the DAD-HDAC3 enzyme for histone substrate. The two SANT motifs synergistically promote histone deacetylation and repression through unique functions. The HID contribution to repression is magnified by its ability to inhibit histone acetyltransferase enzyme activity. Remarkably, the SANT-contg. HID preferentially binds to unacetylated histone tails. This implies that the SMRT HID participates in interpreting the histone code in a feed-forward mechanism that promotes and maintains histone deacetylation at genomic sites of SMRT recruitment.
- 128Hartman, H. B.; Yu, J.; Alenghat, T.; Ishizuka, T.; Lazar, M. A. The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep. 2005, 6, 445– 451, DOI: 10.1038/sj.embor.7400391[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsleru7o%253D&md5=ed0ba38c3767193d2941da0554323805The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3Hartman, Helen B.; Yu, Jiujiu; Alenghat, Theresa; Ishizuka, Takahiro; Lazar, Mitchell A.EMBO Reports (2005), 6 (5), 445-451CODEN: ERMEAX; ISSN:1469-221X. (Nature Publishing Group)Ligands for nuclear receptors facilitate the exchange of co-repressors for coactivators, leading to chromatin modifications that favor the activation of gene transcription. Here, we show that the repressed state of an endogenous retinoic acid-regulated gene is quickly re-established after ligand removal. As expected, repression is characterized by recruitment of N-CoR/SMRT-HDAC3 (histone deacetylase 3) co-repressor complexes, leading to local histone hypoacetylation. The achievement of the repressed state involves the ordered deacetylation of lysines in H4 tails. This order is detd. by the inherent substrate specificity of HDAC3, and unexpectedly predicts the binding preference of N-CoR/SMRT for submaximally acetylated H4 tails. The match between the specificity of acetyl-histone deacetylation by HDAC3 and the histone-binding preference of N-CoR/SMRT allows the co-repressor complex to stabilize and propagate repression of nuclear hormone receptor gene targets.
- 129Bhaskara, S.; Knutson, S. K.; Jiang, G.; Chandrasekharan, M. B.; Wilson, A. J.; Zheng, S.; Yenamandra, A.; Locke, K.; Yuan, J. L.; Bonine-Summers, A. R.; Wells, C. E.; Kaiser, J. F.; Washington, M. K.; Zhao, Z.; Wagner, F. F.; Sun, Z. W.; Xia, F.; Holson, E. B.; Khabele, D.; Hiebert, S. W. HDAC3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 2010, 18, 436– 447, DOI: 10.1016/j.ccr.2010.10.022[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsValtLrM&md5=eecd358b969a1bf6f4c55824c62d2d0fHdac3 Is Essential for the Maintenance of Chromatin Structure and Genome StabilityBhaskara, Srividya; Knutson, Sarah K.; Jiang, Guochun; Chandrasekharan, Mahesh B.; Wilson, Andrew J.; Zheng, Siyuan; Yenamandra, Ashwini; Locke, Kimberly; Yuan, Jia-ling; Bonine-Summers, Alyssa R.; Wells, Christina E.; Kaiser, Jonathan F.; Washington, M. Kay; Zhao, Zhongming; Wagner, Florence F.; Sun, Zu-Wen; Xia, Fen; Holson, Edward B.; Khabele, Dineo; Hiebert, Scott W.Cancer Cell (2010), 18 (5), 436-447CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Summary: Hdac3 is essential for efficient DNA replication and DNA damage control. Deletion of Hdac3 impaired DNA repair and greatly reduced chromatin compaction and heterochromatin content. These defects corresponded to increases in histone H3K9,K14ac; H4K5ac; and H4K12ac in late S phase of the cell cycle, and histone deposition marks were retained in quiescent Hdac3-null cells. Liver-specific deletion of Hdac3 culminated in hepatocellular carcinoma. Whereas HDAC3 expression was downregulated in only a small no. of human liver cancers, the mRNA levels of the HDAC3 cofactor NCOR1 were reduced in 1-third of these cases. SiRNA targeting of NCOR1 and SMRT (NCOR2) increased H4K5ac and caused DNA damage, indicating that the HDAC3/NCOR1/SMRT axis is crit. for maintaining chromatin structure and genomic stability.
- 130Yang, W. M.; Tsai, S. C.; Wen, Y. D.; Fejer, G.; Seto, E. Functional domains of histone deacetylase-3. J. Biol. Chem. 2002, 277, 9447– 9454, DOI: 10.1074/jbc.M105993200[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xitl2kt78%253D&md5=2f4ac16a64de4fcad367111a4bd9eeefFunctional domains of histone deacetylase-3Yang, Wen-Ming; Tsai, Shih-Chang; Wen, Yu-Der; Fejer, Gyorgy; Seto, EdwardJournal of Biological Chemistry (2002), 277 (11), 9447-9454CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Post-translational modifications of histones, in general, and acetylation/deacetylation, in particular, can dramatically alter gene expression in eukaryotic cells. In humans, four highly homologous class I HDAC enzymes (HDAC1, HDAC2, HDAC3, and HDAC8) have been identified to date. Although HDAC3 shares some structural and functional similarities with other class I HDACs, it exists in multisubunit complexes sep. and different from other known HDAC complexes, implying that individual HDACs might function in a distinct manner. In this current study, to understand further the cellular function of HDAC3 and to uncover possible unique roles this protein may have in gene regulation, we performed a detailed anal. of HDAC3 using deletion mutations. Surprisingly, we found that the non-conserved C-terminal region of HDAC3 is required for both deacetylase and transcriptional repression activity. In addn., we discovered that the central portion of the HDAC3 protein possesses a nuclear export signal, whereas the C-terminal part of HDAC3 contributes to the protein's localization in the nucleus. Finally, we found that HDAC3 forms oligomers in vitro and in vivo and that the N-terminal portion of HDAC3 is necessary for this property. These data indicate that HDAC3 comprises sep., non-overlapping domains that contribute to the unique properties and function of this protein.
- 131Watson, P. J.; Fairall, L.; Santos, G. M.; Schwabe, J. W. Structure of HDAC3 bound to corepressor and inositol tetraphosphate. Nature 2012, 481, 335– 340, DOI: 10.1038/nature10728[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsF2rtg%253D%253D&md5=cac4b2efef5360a2a174e31cfb8a241dStructure of HDAC3 bound to co-repressor and inositol tetraphosphateWatson, Peter J.; Fairall, Louise; Santos, Guilherme M.; Schwabe, John W. R.Nature (London, United Kingdom) (2012), 481 (7381), 335-340CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate mol. - D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P4) - acting as an 'intermol. glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator - potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.
- 132Wang, D. F.; Helquist, P.; Wiech, N. L.; Wiest, O. Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem. 2005, 48, 6936– 6947, DOI: 10.1021/jm0505011[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtV2jsLnL&md5=0b59815173df7f16feb9ba66c8b4da83Toward Selective Histone Deacetylase Inhibitor Design: Homology Modeling, Docking Studies, and Molecular Dynamics Simulations of Human Class I Histone DeacetylasesWang, Di-Fei; Helquist, Paul; Wiech, Norbert L.; Wiest, OlafJournal of Medicinal Chemistry (2005), 48 (22), 6936-6947CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, the authors have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homol. model of HDAC8 with the recently published x-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homol. models to understand the similarities and differences between the binding modes. Mol. dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.
- 133Zhang, X.; Zhao, X.; Fiskus, W.; Lin, J.; Lwin, T.; Rao, R.; Zhang, Y.; Chan, J. C.; Fu, K.; Marquez, V. E.; Chen-Kiang, S.; Moscinski, L. C.; Seto, E.; Dalton, W. S.; Wright, K. L.; Sotomayor, E.; Bhalla, K.; Tao, J. Coordinated silencing of Myc-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 2012, 22, 506– 523, DOI: 10.1016/j.ccr.2012.09.003[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFWitLnE&md5=d3a5250f5cbd12b6cc1daaf1893a6f6cCoordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell LymphomasZhang, Xinwei; Zhao, Xiaohong; Fiskus, Warren; Lin, Jianhong; Lwin, Tint; Rao, Rekha; Zhang, Yizhuo; Chan, John C.; Fu, Kai; Marquez, Victor E.; Chen-Kiang, Selina; Moscinski, Lynn C.; Seto, Edward; Dalton, William S.; Wright, Kenneth L.; Sotomayor, Eduardo; Bhalla, Kapil; Tao, JianguoCancer Cell (2012), 22 (4), 506-523CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-assocd. lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create pos. feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.
- 134Li, Y.; Kao, G. D.; Garcia, B. A.; Shabanowitz, J.; Hunt, D. F.; Qin, J.; Phelan, C.; Lazar, M. A. A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity. Genes Dev. 2006, 20, 2566– 2579, DOI: 10.1101/gad.1455006[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVamsr3J&md5=9abb518bd5f86ee9778ba9e0a724c8a9A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activityLi, Yun; Kao, Gary D.; Garcia, Benjamin A.; Shabanowitz, Jeffrey; Hunt, Donald F.; Qin, Jun; Phelan, Caroline; Lazar, Mitchell A.Genes & Development (2006), 20 (18), 2566-2579CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Histone deacetylase (HDAC) inhibitors perturb the cell cycle and have great potential as anti-cancer agents, but their mechanism of action is not well established. HDACs classically function as repressors of gene expression, tethered to sequence-specific transcription factors. Here we report that HDAC3 is a crit., transcription-independent regulator of mitosis. HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes. Deacetylation of H3 in mitosis requires AKAP95/HA95 and HDAC3 and provides a hypoacetylated H3 tail that is the preferred substrate for Aurora B kinase. Phosphorylation of H3S10 by Aurora B leads to dissocn. of HP1 proteins from methylated H3K9 residues on mitotic heterochromatin. This transcription-independent pathway, involving interdependent changes in histone modification and protein assocn., is required for normal progression through mitosis and is an unexpected target of HDAC inhibitors, a class of drugs currently in clin. trials for treating cancer.
- 135Falkenberg, K. J.; Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discovery 2014, 13, 673– 691, DOI: 10.1038/nrd4360[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKrtLjI&md5=ccfb68fa3fd4685e2305cdf8a6a9c81aHistone deacetylases and their inhibitors in cancer, neurological diseases and immune disordersFalkenberg, Katrina J.; Johnstone, Ricky W.Nature Reviews Drug Discovery (2014), 13 (9), 673-691CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small mols. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators - histone deacetylases (HDACs) - and their role in cancer, neurol. diseases and immune disorders. We highlight the development of small-mol. HDAC inhibitors and their use in the lab., in preclin. models and in the clinic.
- 136Minami, J.; Suzuki, R.; Mazitschek, R.; Gorgun, G.; Ghosh, B.; Cirstea, D.; Hu, Y.; Mimura, N.; Ohguchi, H.; Cottini, F.; Jakubikova, J.; Munshi, N. C.; Haggarty, S. J.; Richardson, P. G.; Hideshima, T.; Anderson, K. C. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia 2014, 28, 680– 689, DOI: 10.1038/leu.2013.231[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWru7%252FK&md5=4ff22875205c892a7bc8c82e2aa4bdd0Histone deacetylase 3 as a novel therapeutic target in multiple myelomaMinami, J.; Suzuki, R.; Mazitschek, R.; Gorgun, G.; Ghosh, B.; Cirstea, D.; Hu, Y.; Mimura, N.; Ohguchi, H.; Cottini, F.; Jakubikova, J.; Munshi, N. C.; Haggarty, S. J.; Richardson, P. G.; Hideshima, T.; Anderson, K. C.Leukemia (2014), 28 (3), 680-689CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Histone deacetylases (HDACs) represent novel mol. targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable antitumor activities in the preclin. setting; however, their clin. utility is limited because of unfavorable toxicities assocd. with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small-mol. HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and poly (ADP-ribose) polymerase cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of signal transducers and activators of transcription 3 (STAT3). Neither interleukin-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on phospho-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or 2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.
- 137Leus, N. G. J.; Zwinderman, M. R. H.; Dekker, F. J. Histone deacetylase 3 (HDAC3) as emerging drug target in NF-κB-mediated inflammation. Curr. Opin. Chem. Biol. 2016, 33, 160– 168, DOI: 10.1016/j.cbpa.2016.06.019[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsF2qt7bO&md5=32cad5b6e5fe7f0b23903b9a893d4809Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammationLeus, Niek G. J; Zwinderman, Martijn R. H; Dekker, Frank J.Current Opinion in Chemical Biology (2016), 33 (), 160-168CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications is lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small mols. that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addn., we address the application of frequently used small mol. HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chem. efforts aimed at HDAC 3-selective inhibitors are discussed.
- 138Angiolilli, C.; Kabala, P. A.; Grabiec, A. M.; Van Baarsen, I. M.; Ferguson, B. S.; García, S.; Malvar Fernandez, B.; McKinsey, T. A.; Tak, P. P.; Fossati, G.; Mascagni, P.; Baeten, D. L.; Reedquist, K. A. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann. Rheum. Dis. 2017, 76, 277– 285, DOI: 10.1136/annrheumdis-2015-209064[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFaiurk%253D&md5=3ed3855cc03247206f63ba518b19f12bHistone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytesAngiolilli, Chiara; Kabala, Pawel A.; Grabiec, Aleksander M.; Van Baarsen, Iris M.; Ferguson, Bradley S.; Garcia, Samuel; Fernandez, Beatriz Malvar; McKinsey, Timothy A.; Tak, Paul P.; Fossati, Gianluca; Mascagni, Paolo; Baeten, Dominique L.; Reedquist, Kris A.Annals of the Rheumatic Diseases (2017), 76 (1), 277-285CODEN: ARDIAO; ISSN:0003-4967. (BMJ Publishing Group)Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblastlike synoviocytes (FLS). RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)- α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quant. PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN prodn. and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN prodn. in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
- 139Weïwer, M.; Lewis, M. C.; Wagner, F. F.; Holson, E. B. Therapeutic potential of isoform selective HDAC inhibitors for the treatment of schizophrenia. Future Med. Chem. 2013, 5, 1491– 1508, DOI: 10.4155/fmc.13.141[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWrsrvF&md5=64ccc93601eb4b9f1321bd4f8fa6258cTherapeutic potential of isoform selective HDAC inhibitors for the treatment of schizophreniaWeiwer, Michel; Lewis, Michael C.; Wagner, Florence F.; Holson, Edward B.Future Medicinal Chemistry (2013), 5 (13), 1491-1508CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Increasing evidence supports a role for epigenetic involvement in some of the neurobiol. alterations obsd. in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Addnl. data support the notion that small mol. inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms assocd. with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the assocd. biol. effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.
- 140Kuboyama, T.; Wahane, S.; Huang, Y.; Zhou, X.; Wong, J. K.; Koemeter-Cox, A.; Martini, M.; Friedel, R. H.; Zou, H. HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. Sci. Rep. 2017, 7, 8641, DOI: 10.1038/s41598-017-08535-4[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfpsVKqug%253D%253D&md5=59b8a9bfa8a91042ea92866073a6f6a4HDAC3 inhibition ameliorates spinal cord injury by immunomodulationKuboyama Tomoharu; Wahane Shalaka; Huang Yong; Zhou Xiang; Wong Jamie K; Koemeter-Cox Andrew; Martini Michael; Friedel Roland H; Zou Hongyan; Kuboyama Tomoharu; Wong Jamie K; Koemeter-Cox Andrew; Friedel Roland H; Zou HongyanScientific reports (2017), 7 (1), 8641 ISSN:.Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.
- 141Chen, S.; Ye, J.; Chen, X.; Shi, J.; Wu, W.; Lin, W.; Lin, W.; Li, Y.; Fu, H.; Li, S. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J. Neuroinflammation 2018, 15, 150, DOI: 10.1186/s12974-018-1193-6[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWgur%252FP&md5=18c51bab4fe7872913cc9e9285cc0e5eValproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3Chen, Shoubo; Ye, Jingfang; Chen, Xiangrong; Shi, Jinnan; Wu, Wenhua; Lin, Wenping; Lin, Weibin; Li, Yasong; Fu, Huangde; Li, ShunJournal of Neuroinflammation (2018), 15 (), 150/1-150/14CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)Background: Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF- κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential mol. mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment. Methods: The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to det. the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot anal. were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI. Results: The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI. Conclusions: These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.
- 142Kwapis, J. L.; Alaghband, Y.; Kramár, E. A.; López, A. J.; Vogel Ciernia, A.; White, A. O.; Shu, G.; Rhee, D.; Michael, C. M.; Montellier, E.; Liu, Y.; Magnan, C. N.; Chen, S.; Sassone-Corsi, P.; Baldi, P.; Matheos, D. P.; Wood, M. A. Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat. Commun. 2018, 9, 3323, DOI: 10.1038/s41467-018-05868-0[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3gtVOjug%253D%253D&md5=1a2b79c97f7108ddfef8a25ed31e50c7Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memoryKwapis Janine L; Alaghband Yasaman; Kramar Eniko A; Lopez Alberto J; Shu Guanhua; Rhee Diane; Michael Christina M; Matheos Dina P; Wood Marcelo A; Kwapis Janine L; Alaghband Yasaman; Kramar Eniko A; Lopez Alberto J; Shu Guanhua; Rhee Diane; Michael Christina M; Matheos Dina P; Wood Marcelo A; Kwapis Janine L; Wood Marcelo A; Vogel Ciernia Annie; White Andre O; Montellier Emilie; Sassone-Corsi Paolo; Liu Yu; Magnan Christophe N; Chen Siwei; Baldi Pierre; Liu Yu; Magnan Christophe N; Chen Siwei; Baldi PierreNature communications (2018), 9 (1), 3323 ISSN:.Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and experience-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.
- 143Kuta, R.; Larochelle, N.; Fernandez, M.; Pal, A.; Minotti, S.; Tibshirani, M.; St. Louis, K.; Gentil, B. J.; Nalbantoglu, J. N.; Hermann, A.; Durham, H. D. Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models. Cell Stress Chaperones 2020, 25, 173– 191, DOI: 10.1007/s12192-019-01064-1[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmtVyqsQ%253D%253D&md5=6027a7e2f074f7935a2fca9062b317d9Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS modelsKuta, Rachel; Larochelle, Nancy; Fernandez, Mario; Pal, Arun; Minotti, Sandra; Tibshirani, Michael; St. Louis, Kyle; Gentil, Benoit J.; Nalbantoglu, Josephine N.; Hermann, Andreas; Durham, Heather D.Cell Stress & Chaperones (2020), 25 (1), 173-191CODEN: CSCHFG; ISSN:1355-8145. (Springer)Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.
- 144Nghia, N. A.; Hirasawa, T.; Kasai, H.; Obata, C.; Moriishi, K.; Mochizuki, K.; Koizumi, S.; Kubota, T. Long-term imipramine treatment increases N-methyl-d-aspartate receptor activity and expression via epigenetic mechanisms. Eur. J. Pharmacol. 2015, 752, 69– 77, DOI: 10.1016/j.ejphar.2015.02.010[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1arur8%253D&md5=32fa23fb10469f6c5093f04bcd727d76Long-term imipramine treatment increases N-methyl-D-aspartate receptor activity and expression via epigenetic mechanismsNghia, Nguyen An; Hirasawa, Takae; Kasai, Hirotake; Obata, Chie; Moriishi, Kohji; Mochizuki, Kazuki; Koizumi, Schuichi; Kubota, TakeoEuropean Journal of Pharmacology (2015), 752 (), 69-77CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-D-aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30 s) imipramine treatment decreased Ca2+ influx through NMDA receptors, whereas long-term treatment (48 h) increased Ca2+ influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect.
- 145Venkatraman, A.; Hu, Y. S.; Didonna, A.; Cvetanovic, M.; Krbanjevic, A.; Bilesimo, P.; Opal, P. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum. Mol. Genet. 2014, 23, 3733– 3745, DOI: 10.1093/hmg/ddu081[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVentLjO&md5=3ed40191561c696b23873f49095f53a2The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro; Cvetanovic, Marija; Krbanjevic, Aleksandar; Bilesimo, Patrice; Opal, PuneetHuman Molecular Genetics (2014), 23 (14), 3733-3745CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease caused by a pathogenic glutamine repeat expansion in the protein ataxin-1 (ATXN1). One likely mechanism mediating pathogenesis is excessive transcriptional repression induced by the expanded ATXN-1. Because ATXN1 binds HDAC3, a Class I histone deacetylase (HDAC) that we have found to be required for ATXN1-induced transcriptional repression, we tested whether genetically depleting HDAC3 improves the phenotype of the SCA1 knock-in mouse (SCA1154Q/2Q), the most physiol. relevant model of SCA1. Given that HDAC3 null mice are embryonic lethal, we used for our analyses a combination of HDAC3 haploinsufficient and Purkinje cell (PC)-specific HDAC3 null mice. Although deleting a single allele of HDAC3 in the context of SCA1 was insufficient to improve cerebellar and cognitive deficits of the disease, a complete loss of PC HDAC3 was highly deleterious both behaviorally, with mice showing early onset ataxia, and pathol., with progressive histol. evidence of degeneration. Inhibition of HDAC3 may yet have a role in SCA1 therapy, but our study provides cautionary evidence that this approach could produce untoward effects. Indeed, the neurotoxic consequences of HDAC3 depletion could prove relevant, wherever pharmacol. inhibition of HDAC3 is being contemplated, in disorders ranging from cancer to neurodegeneration.
- 146Choi, H. K.; Choi, Y.; Kang, H.; Lim, E. J.; Park, S. Y.; Lee, H. S.; Park, J. M.; Moon, J.; Kim, Y. J.; Choi, I.; Joe, E. H.; Choi, K. C.; Yoon, H. G. PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death. Hum. Mol. Genet. 2015, 24, 1127– 1141, DOI: 10.1093/hmg/ddu526[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVylsL3P&md5=078a2d9bff16f9aebb0b4189830c040fPINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell deathChoi, Hyo-Kyoung; Choi, Youngsok; Kang, Hee Bum; Lim, Eun-jin; Park, Soo-Yeon; Lee, Hyun-Seob; Park, Ji-Min; Moon, Jisook; Kim, Yoon-Jung; Choi, Insup; Joe, Eun-Hye; Choi, Kyung-Chul; Yoon, Ho-GeunHuman Molecular Genetics (2015), 24 (4), 1127-1141CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Deciphering the mol. basis of neuronal cell death is a central issue in the etiol. of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the mol. basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct assocn. with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3S424E substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.
- 147Bardai, F. H.; Verma, P.; Smith, C.; Rawat, V.; Wang, L.; D’Mello, S. R. Disassociation of histone deacetylase-3 from normal huntingtin underlies mutant huntingtin neurotoxicity. J. Neurosci. 2013, 33, 11833– 11838, DOI: 10.1523/JNEUROSCI.5831-12.2013[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKqu77F&md5=f5d39b1df5ef060d99bf39d9bdb28a2cDisassociation of histone deacetylase-3 from normal Huntingtin underlies mutant huntingtin neurotoxicityBardai, Farah H.; Verma, Pragya; Smith, Chad; Rawat, Varun; Wang, Lulu; D'Mello, Santosh R.Journal of Neuroscience (2013), 33 (29), 11833-11838CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Huntington's disease (HD) is caused by a polyglutamine expansion within the huntingtin (Htt) protein. Both loss of function of normal Htt and gain of a toxic function by the polyglutamine-expanded mutant Htt protein have been proposed to be responsible for HD, although the mol. mechanisms involved are unclear. We show that Htt is a neuroprotective protein in both HD-related and unrelated model systems. Neuroprotection by Htt is mediated by its sequestration of histone deacetylase-3 (HDAC3), a protein known to promote neuronal death. In contrast to the normal Htt, mutant Htt interacts poorly with HDAC3. However, expression of mutant Htt liberates HDAC3 from Htt, thus de-repressing its neurotoxic activity. Indeed, mutant Htt neurotoxicity is inhibited by the knockdown of HDAC3 and markedly reduced in HDAC3-deficient neurons. A redn. in Htt-HDAC3 interaction is also seen in neurons exposed to other apoptotic stimuli and in the striatum of R6/2 HD mice. Our results suggest that the robust interaction between Htt and HDAC3 along with the ability of mutant Htt to disrupt this assocn. while not itself interacting with HDAC3 provides an explanation for both the loss-of-function and gain-of-toxic-function mechanisms proposed for HD. Moreover, our results identify HDAC3 as an essential player in mutant Htt-induced neurodegeneration.
- 148Jia, H.; Pallos, J.; Jacques, V.; Lau, A.; Tang, B.; Cooper, A.; Syed, A.; Purcell, J.; Chen, Y.; Sharma, S.; Sangrey, G. R.; Darnell, S. B.; Plasterer, H.; Sadri-Vakili, G.; Gottesfeld, J. M.; Thompson, L. M.; Rusche, J. R.; Marsh, J. L.; Thomas, E. A. Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine elicited phenotypes in model systems of Huntington’s disease. Neurobiol. Dis. 2012, 46, 351– 361, DOI: 10.1016/j.nbd.2012.01.016[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xltlagu7w%253D&md5=eb0b2461d8059ed525e3c477db32430dHistone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's diseaseJia, Haiqun; Pallos, Judit; Jacques, Vincent; Lau, Alice; Tang, Bin; Cooper, Andrew; Syed, Adeela; Purcell, Judith; Chen, Yi; Sharma, Shefali; Sangrey, Gavin R.; Darnell, Shayna B.; Plasterer, Heather; Sadri-Vakili, Ghazaleh; Gottesfeld, Joel M.; Thompson, Leslie M.; Rusche, James R.; Marsh, J. Lawrence; Thomas, Elizabeth A.Neurobiology of Disease (2012), 46 (2), 351-361CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compds. against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathol. in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-time PCR anal. to detect expression differences for 13 HD-related genes. We find that HDACi 4b and 136, two compds. showing high potency for inhibiting HDAC3 were most effective in reversing the expression of genes relevant to HD, including Ppp1r1b, which encodes DARPP-32, a marker for medium spiny striatal neurons. In contrast, compds. targeting HDAC1 were less effective at correcting gene expression abnormalities in R6/2 transgenic mice, but did cause significant increases in the expression of selected genes. An addnl. panel of 4b-related compds. was tested in a Drosophila model of HD and in STHdh Q111 striatal cells to further distinguish HDAC selectivity. Significant improvement in huntingtin-elicited Drosophila eye neurodegeneration in the fly was obsd. in response to treatment with compds. targeting human HDAC1 and/or HDAC3. In STHdh Q111 striatal cells, the ability of HDAC inhibitors to improve huntingtin-elicited metabolic deficits correlated with the potency at inhibiting HDAC1 and HDAC3, although the IC50 values for HDAC1 inhibition were typically 10-fold higher than for inhibition of HDAC3. Assessment of HDAC protein localization in brain tissue by Western blot anal. revealed accumulation of HDAC1 and HDAC3 in the nucleus of HD transgenic mice compared to wt mice, with a concurrent decrease in cytoplasmic localization, suggesting that these HDACs contribute to a repressive chromatin environment in HD. No differences were detected in the localization of HDAC2, HDAC4 or HDAC7. These results suggest that inhibition of HDACs 1 and 3 can relieve HD-like phenotypes in model systems and that HDAC inhibitors targeting these isotypes might show therapeutic benefit in human HD.
- 149Janczura, K. J.; Volmar, C. H.; Sartor, G. C.; Rao, S. J.; Ricciardi, N. R.; Lambert, G.; Brothers, S. P.; Wahlestedt, C. Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E11148– E11157, DOI: 10.1073/pnas.1805436115[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1CrtrrP&md5=f36c313cbc1bb2c7dc7cc1590351cb18Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse modelJanczura, Karolina J.; Volmar, Claude-Henry; Sartor, Gregory C.; Rao, Sunil J.; Ricciardi, Natalie R.; Lambert, Guerline; Brothers, Shaun P.; Wahlestedt, ClaesProceedings of the National Academy of Sciences of the United States of America (2018), 115 (47), E11148-E11157CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Alzheimer's disease (AD) the leading cause of age-related dementia. Neuropathol. hallmarks of AD include brain deposition of β-amyloid plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-assocd. sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1-42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathol. tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1-42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1-42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEe4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins assocd. with AD pathophysiol., supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
- 150Zhu, X.; Wang, S.; Yu, L.; Jin, J.; Ye, X.; Liu, Y.; Xu, Y. HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease. Aging Cell 2017, 16, 1073– 1082, DOI: 10.1111/acel.12642[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OhsrzN&md5=46f797519fd4f22e253f3decf83fe8ecHDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's diseaseZhu, Xiaolei; Wang, Sulei; Yu, Linjie; Jin, Jiali; Ye, Xing; Liu, Yi; Xu, YunAging Cell (2017), 16 (5), 1073-1082CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)Summary : The accumulation and deposition of beta-amyloid (Aβ) is a key neuropathol. hallmark of Alzheimer's disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms assocd. with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6- and 9-mo-old APPswe/PS1dE9 (APP/PS1) mice compared with that in age-matched wild-type C57BL/6 (B6) mice. Lentivirus -mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine d., glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine d. is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9-mo-old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine d. in 6-mo-old APP/PS1 mice. In conclusion, our results indicate that HDAC3 neg. regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.
- 151Lee, H. A.; Lee, D. Y.; Cho, H. M.; Kim, S. Y.; Iwasaki, Y.; Kim, I. K. Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ. Res. 2013, 112, 1004– 1012, DOI: 10.1161/CIRCRESAHA.113.301071[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkvVKjtbo%253D&md5=a4b417602f9ce64414c642b83ea661c9Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through Its Acetylation and Prevents Development of HypertensionLee, Hae-Ahm; Lee, Dong-Youb; Cho, Hyun-Min; Kim, Sang-Yeob; Iwasaki, Yasumasa; Kim, In KyeomCirculation Research (2013), 112 (7), 1004-1012CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate-induced hypertensive rats and spontaneously hypertensive rats. However, the mol. mechanism remains elusive. Objective: We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats. Methods and results: Expression of MR target genes was measured by quant. real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunopptn. assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was detd. by Western blot with anti-acetyl-lysine antibody after immunopptn. with anti-MR antibody. Transcriptional activity of MR was detd. by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received s.c. injection of 40 mg/kg per wk of deoxycorticosterone acetate and drinking water contg. 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II on promoters of target genes. HDAC inhibition promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids. Conclusions: These results indicate that HDAC inhibition attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats.
- 152Nozik-Grayck, E.; Woods, C.; Stearman, R. S.; Venkataraman, S.; Ferguson, B. S.; Swain, K.; Bowler, R. P.; Geraci, M. W.; Ihida-Stansbury, K.; Stenmark, K. R.; McKinsey, T. A.; Domann, F. E. Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 2016, 311, L124– L1234, DOI: 10.1152/ajplung.00263.2015
- 153Zampetaki, A.; Zeng, L.; Margariti, A.; Xiao, Q.; Li, H.; Zhang, Z.; Pepe, A. E.; Wang, G.; Habi, O.; deFalco, E.; Cockerill, G.; Mason, J. C.; Hu, Y.; Xu, Q. Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow. Circulation 2010, 121, 132– 142, DOI: 10.1161/CIRCULATIONAHA.109.890491[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1WjtrjF&md5=1d871191f2a860279e21de80bce243ddHistone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed FlowZampetaki, Anna; Zeng, Lingfang; Margariti, Andriana; Xiao, Qingzhong; Li, Hongling; Zhang, Zhongyi; Pepe, Anna Elena; Wang, Gang; Habi, Ouassila; de Falco, Elena; Cockerill, Gillian; Mason, Justin C.; Hu, Yanhua; Xu, QingboCirculation (2010), 121 (1), 132-142CODEN: CIRCAZ; ISSN:0009-7322. (Lippincott Williams & Wilkins)Background-Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development. Methods and Results-En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was obsd. in endothelial cells exposed to disturbed flow in vitro. Interestingly, phosphorylation of HDAC3 at serine/threonine was obsd. in these cells, suggesting that disturbed flow leads to posttranscriptional modification and stabilization of the HDAC3 protein. Coimmunopptn. expts. showed that HDAC3 and Akt form a complex. Using a series of constructs harboring deletions, we found residues 136 to 206 of HDAC3 to be crucial in this interaction. Enforced expression of HDAC3 resulted in increased phosphorylation of Akt and upregulation of its kinase activity. In line with these findings, knockdown of HDAC3 with lentiviral vectors (shHDAC3) led to a dramatic decrease in cell survival accompanied by apoptosis in endothelial cells. In aortic isografts of apolipoprotein E-knockout mice treated with shHDAC3, a robust atherosclerotic lesion was formed. Surprisingly, 3 of the 8 mice that received shHDAC3-infected grafts died within 2 days after the operation. Miller staining of the isografts revealed disruption of the basement membrane and rupture of the vessel. Conclusions-Our findings demonstrated that HDAC3 serves as an essential prosurvival mol. with a crit. role in maintaining the endothelial integrity via Akt activation and that severe atherosclerosis and vessel rupture in isografted vessels of apolipoprotein E-knockout mice occur when HDAC3 is knocked down.
- 154Dirice, E.; Ng, R.; Martinez, R.; Hu, J.; Wagner, F. F.; Holson, E. B.; Wagner, B. K.; Kulkarni, R. N. Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes. J. Biol. Chem. 2017, 292, 17598– 17608, DOI: 10.1074/jbc.M117.804328[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslehsrfI&md5=b05649e9b132289bd49ad76398f6615cIsoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetesDirice, Ercument; Ng, Raymond W. S.; Martinez, Rachael; Hu, Jiang; Wagner, Florence F.; Holson, Edward B.; Wagner, Bridget K.; Kulkarni, Rohit N.Journal of Biological Chemistry (2017), 292 (43), 17598-17608CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro. In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo. We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 wk to female nonobese diabetic (NOD) mice, beginning at 3 wk of age, followed by twice-weekly injections until age 25 wk, protects the animals from diabetes. The preservation of β-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro. All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing addnl. evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased nos. of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.
- 155Meier, B. C.; Wagner, B. K. Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. Epigenomics 2014, 6, 209– 214, DOI: 10.2217/epi.14.11[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnslClt7g%253D&md5=e6342f84c653e4d32e272e736789e2b1Inhibition of HDAC3 as a strategy for developing novel diabetes therapeuticsMeier, Bennett C.; Wagner, Bridget K.Epigenomics (2014), 6 (2), 209-214CODEN: EPIGC7; ISSN:1750-192X. (Future Medicine Ltd.)A review. Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. Recent studies have put a greater spotlight on metabolic diseases, in particular Type 1 and Type 2 diabetes, as potential indications for which HDAC inhibition could be beneficial. Evidence suggests that inhibition of HDAC3 protects β-cells from cytokine-induced apoptosis, an important event in the development of Type 1 diabetes. On the other hand, the pathogenesis of Type 2 diabetes involves a combination of peripheral insulin resistance and pancreatic β-cell failure. Again, data from the literature indicate that HDAC3 regulates genes involved in key metabolic events. Together, these results suggest that selective inhibition of HDAC3 may be an attractive strategy for targeting these diseases.
- 156Chen, W. B.; Gao, L.; Wang, J.; Wang, Y. G.; Dong, Z.; Zhao, J.; Mi, Q. S.; Zhou, L. Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. Oncotarget 2016, 7, 57485– 57497, DOI: 10.18632/oncotarget.11295[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szitFKluw%253D%253D&md5=4d3ed8a674b52a02db968b6420ce0dffConditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetesChen Wen-Bin; Wang Jie; Mi Qing-Sheng; Zhou Li; Chen Wen-Bin; Gao Ling; Chen Wen-Bin; Wang Jie; Mi Qing-Sheng; Zhou Li; Wang Jie; Wang Yan-Gang; Dong Zheng; Zhao Jiajun; Mi Qing-Sheng; Zhou LiOncotarget (2016), 7 (36), 57485-57497 ISSN:.Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 knockout and wild type littermate controls. Mice with β-cell-specific HDAC3 deletion displayed decreased pancreatic insulin content, disrupted glucose-stimulated insulin secretion, with intermittent spontaneous diabetes and dramatically enhanced susceptibility to STZ-induced diabetes. Furthermore, islet β-cell line, MIN6 cells with siRNA-mediated HDAC3 silence, showed decreased insulin gene transcription, which was mediated, at least partially, through the upregulation of suppressors of cytokine signaling 3 (SOCS3). These results indicate the critical role of HDAC3 in normal β-cell differentiation, maintenance and function.
- 157Maubon, D.; Bougdour, A.; Wong, Y. S.; Brenier-Pinchart, M. P.; Curt, A.; Hakimi, M. A.; Pelloux, H. Activity of histone deacetylase inhibitor FR235222 on Taxoplasma gonidii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. Antimicrob. Agents Chemother. 2010, 54, 4843– 4850, DOI: 10.1128/AAC.00462-10[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVCitrrF&md5=9cac7e307f59c9bbb90ac01985540648Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compoundsMaubon, Daniele; Bougdour, Alexandre; Wong, Yung-Sing; Brenier-Pinchart, Marie-Pierre; Curt, Aurelie; Hakimi, Mohamed-Ali; Pelloux, HerveAntimicrobial Agents and Chemotherapy (2010), 54 (11), 4843-4850CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compd. is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compd. is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compd. impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 deriv. compds. We identified two new mols. that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivs. as new lead compds. in the range of therapeutics available for acute and chronic toxoplasmosis.
- 158Farhat, D. C.; Swale, C.; Dard, C.; Cannella, D.; Ortet, P.; Barakat, M.; Sindikubwabo, F.; Belmudes, L.; De Bock, P. J.; Couté, Y.; Bougdour, A.; Hakimi, M. A. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment. Nat. Microbiol. 2020, 5, 570– 583, DOI: 10.1038/s41564-020-0674-4[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvFyitLc%253D&md5=66b293770e5c3857bec274fa06266fafA MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitmentFarhat, Dayana C.; Swale, Christopher; Dard, Celine; Cannella, Dominique; Ortet, Philippe; Barakat, Mohamed; Sindikubwabo, Fabien; Belmudes, Lucid; De Bock, Pieter-Jan; Coute, Yohann; Bougdour, Alexandre; Hakimi, Mohamed-AliNature Microbiology (2020), 5 (4), 570-583CODEN: NMAICH; ISSN:2058-5276. (Nature Research)Abstr.: Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reprodn., which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.
- 159Huber, K.; Doyon, G.; Plaks, J.; Fyne, E.; Mellors, J. W.; Sluis-Cremer, N. Inhibitors of histone deacetylases correlation between isoform specificity and reactivation of type 1 (HIV-1) from latently infected cells. J. Biol. Chem. 2011, 286, 22211– 22218, DOI: 10.1074/jbc.M110.180224[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXns1Kks7Y%253D&md5=1d62cae8ca4609975bb0082ce17fd73bInhibitors of Histone Deacetylases: Correlation Between Isoform Specificity and Reactivation of HIV Type 1 (HIV-1) From Latently Infected CellsHuber, Kelly; Doyon, Genevieve; Plaks, Joseph; Fyne, Elizabeth; Mellors, John W.; Sluis-Cremer, NicolasJournal of Biological Chemistry (2011), 286 (25), 22211-22218CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chem. approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunopptn. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC50 = 5.5 mM) relative to HDAC1 (IC50 = 170 μM). Because the total therapeutic concn. of valproic acid ranges from 275 to 700 μM in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chem. approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.
- 160Romani, B.; Kamali Jamil, R.; Hamidi-Fard, M.; Rahimi, P.; Momen, S. B.; Aghasadeghi, M. R.; Allahbakhshi, E. HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin. Sci. Rep. 2016, 6, 31924, DOI: 10.1038/srep31924[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSrsb3I&md5=45ca690a1dee464d6002b84708cc5b30HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatinRomani, Bizhan; Kamali Jamil, Razieh; Hamidi-Fard, Mojtaba; Rahimi, Pooneh; Momen, Seyed Bahman; Aghasadeghi, Mohammad Reza; Allahbakhshi, ElhamScientific Reports (2016), 6 (), 31924CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)HIV-1 Vpr is an accessory protein that induces proteasomal degrdn. of multiple proteins. We recently showed that Vpr targets class I HDACs on chromatin for proteasomal degrdn. Here we show that Vpr induces degrdn. of HDAC1 and HDAC3 in HIV-1 latently infected J-Lat cells. Degrdn. of HDAC1 and HDAC3 was also obsd. on the HIV-1 LTR and as a result, markers of active transcription were recruited to the viral promoter and induced viral activation. Knockdown of HDAC1 and HDAC3 activated the latent HIV-1 provirus and complementation with HDAC3 inhibited Vpr-induced HIV-1 reactivation. Viral reactivation and degrdn. of HDAC1 and HDAC3 was conserved among Vpr proteins of HV-1 group M. Serum Vpr isolated from patients or the release of virion-incorporated Vpr from viral lysates also activated HIV-1 in latently infected cell lines and PBMCs from HIV-1 infected patients. Our results indicate that Vpr counteracts HIV-1 latency by inducing proteasomal degrdn. of HDAC1 and 3 leading to reactivation of the viral promoter.
- 161Romani, B.; Baygloo, N. S.; Hamidi-Fard, M.; Aghasadeghi, M. R.; Allahbakhshi, E. HIV-1 Vpr protein induces proteasomal degradation of chromatin-associated class I HDACs to overcome latent infection of macrophages. J. Biol. Chem. 2016, 291, 2696– 2711, DOI: 10.1074/jbc.M115.689018[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVOqtrk%253D&md5=c2749945626e80cd7d5662b3f3ffd39bHIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of MacrophagesRomani, Bizhan; Baygloo, Nima Shaykh; Hamidi-Fard, Mojtaba; Aghasadeghi, Mohammad Reza; Allahbakhshi, ElhamJournal of Biological Chemistry (2016), 291 (6), 2696-2711CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here the authors show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. The authors found that Vpr binds and depletes chromatin-assocd. class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. De novo expression of Vpr in infected macrophages induced depletion of HDAC1 and 3 on the HIV-1 LTR that was assocd. with hyperacetylation of histones on the HIV-1 LTR. As a result of hyperacetylation of histones on HIV-1 promotor, the virus established an active promotor and this contributed to the acute infection of macrophages. Collectively, HIV-1 Vpr down-regulates class I HDACs on chromatin to counteract latent infections of macrophages.
- 162Bhaskara, S.; Chyla, B. J.; Amann, J. M.; Knutson, S. K.; Cortez, D.; Sun, Z. W.; Hiebert, S. W. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 2008, 30, 61– 72, DOI: 10.1016/j.molcel.2008.02.030[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFegurY%253D&md5=6b54eb096e03b39fa255c0ce5a213035Deletion of Histone deacetylase 3 reveals critical roles in S phase progression and DNA damage controlBhaskara, Srividya; Chyla, Brenda J.; Amann, Joseph M.; Knutson, Sarah K.; Cortez, David; Sun, Zu-Wen; Hiebert, Scott W.Molecular Cell (2008), 30 (1), 61-72CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a crit. component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were obsd. in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was obsd. in Hdac3-/- interphase cells, which appears to be assocd. with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.
- 163Nishimoto, K.; Niida, H.; Uchida, C.; Ohhata, T.; Kitagawa, K.; Motegi, A.; Suda, T.; Kitagawa, M. HDAC3 is required for XPC recruitment and nucleotide excision repair of DNA damage induced by UV irradiation. Mol. Cancer Res. 2020, 18, 1367– 1378, DOI: 10.1158/1541-7786.MCR-20-0214[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1SitLfM&md5=e4191c0c8f2d2b23ba564496ae2f02cbHDAC3 is required for XPC recruitment and nucleotide excision repair of DNA damage induced by UV irradiationNishimoto, Koji; Niida, Hiroyuki; Uchida, Chiharu; Ohhata, Tatsuya; Kitagawa, Kyoko; Motegi, Akira; Suda, Takafumi; Kitagawa, MasatoshiMolecular Cancer Research (2020), 18 (9), 1367-1378CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradn. Depletion of HDAC3 caused defects in cyclobutene pyrimidine dimer excision and sensitized cells to UV irradn. HDAC3-depleted cells had impaired unscheduled DNA synthesis, but not recovery of RNA synthesis, which indicates that HDAC3 was required for global genome NER. Moreover, xeroderma pigmentosum, complementation group C (XPC) accumulation at the local UV-irradiated area was attenuated in HDAC3-depleted cells. In addn. to the delay of XPC accumulation at DNA damage sites, XPC ubiquitylation was inhibited in HDAC3-depleted cells. These results suggest that the deacetylation of histone H3K14 by HDAC3 after UV irradn. contributes to XPC recruitment to DNA lesions to promote global genome NER. Implications: Involvement of histone deacetylation for XPC accumulation after UV irradn. indicates conversion of chromatin structure is essential for nucleotide excision repair in human cancer cells.
- 164Long, J.; Fang, W. Y.; Chang, L.; Gao, W. H.; Shen, Y.; Jia, M. Y.; Zhang, Y. X.; Wang, Y.; Dou, H. B.; Zhang, W. J.; Zhu, J.; Liang, A. B.; Li, J. M.; Hu, J. Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response. Leukemia 2017, 31, 2761– 2770, DOI: 10.1038/leu.2017.130[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVyiu74%253D&md5=bb06860d8d48faa24985aa0257d9da1fTargeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage responseLong, J.; Fang, W. Y.; Chang, L.; Gao, W. H.; Shen, Y.; Jia, M. Y.; Zhang, Y. X.; Wang, Y.; Dou, H. B.; Zhang, W. J.; Zhu, J.; Liang, A. B.; Li, J. M.; Hu, JiongLeukemia (2017), 31 (12), 2761-2770CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases (HDAC) are important regulators to maintain chromatin structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, esp. under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addn. to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells. Using genetic and pharmacol. approaches, we show that HDAC3 contributes to chemotherapy resistance by regulating the activation of AKT, a well-documented factor in drug resistance development. HDAC3 binds to AKT and deacetylates it at the site Lys20, thereby promoting the phosphorylation of AKT. Chemotherapy drug exposure enhances the interaction between HDAC3 and AKT, resulting in decrease in AKT acetylation and increase in AKT phosphorylation. Whereas HDAC3 depletion or inhibition abrogates these responses and meanwhile sensitizes leukemia cells to chemotoxicity-induced apoptosis. Importantly, in vivo HDAC3 suppression reduces leukemia progression and sensitizes MLL-AF9+ leukemia to chemotherapy. Our findings suggest that combination therapy with HDAC3 inhibitor and genotoxic agents may constitute a successful strategy for overcoming chemotherapy resistance.
- 165Li, X.; Inks, E. S.; Li, X.; Hou, J.; Chou, C. J.; Zhang, J.; Jiang, Y.; Zhang, Y.; Xu, W. Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity. J. Med. Chem. 2014, 57, 3324– 3341, DOI: 10.1021/jm401877m[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsFOjsr4%253D&md5=4e86a4e7c9fda199bdd3cb12730db1daDiscovery of the First N-Hydroxycinnamamide-Based Histone Deacetylase 1/3 Dual Inhibitors with Potent Oral Antitumor ActivityLi, Xiaoyang; Inks, Elizabeth S.; Li, Xiaoguang; Hou, Jinning; Chou, C. James; Zhang, Jian; Jiang, Yuqi; Zhang, Yingjie; Xu, WenfangJournal of Medicinal Chemistry (2014), 57 (8), 3324-3341CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based histone deacetylase inhibitors (HDACIs), among which the representative compd. I exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using I as lead, among which, compd. II gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Several of these compds. showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compd. II as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.
- 166Spurling, C. C.; Godman, C. A.; Noonan, E. J.; Rasmussen, T. P.; Rosenberg, D. W.; Giardina, C. HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol. Carcinog. 2008, 47, 137– 147, DOI: 10.1002/mc.20373[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXit1Sgtrc%253D&md5=2c4b1c714668ffe205c71fda2cff368fHDAC3 overexpression and colon cancer cell proliferation and differentiationSpurling, Colleen C.; Godman, Cassandra A.; Noonan, Emily J.; Rasmussen, Theodore P.; Rosenberg, Daniel W.; Giardina, CharlesMolecular Carcinogenesis (2008), 47 (2), 137-147CODEN: MOCAE8; ISSN:0899-1987. (Wiley-Liss, Inc.)An immunohistochem. anal. of human colorectal adenocarcinomas showed that cancer cells express widely varying levels of HDAC3. The SW480 colon cancer cell line was found to express high levels of HDAC3 compared to other colon cancer cell lines. P21 was poorly induced in SW480 cells relative to the lower HDAC3-expressing HT-29 cells. RNAi-induced redn. of HDAC3 in SW480 cells increased their constitutive, butyrate-, TSA-, and TNF-α-induced expression of p21, but did not cause all the gene expression changes induced upon general histone deacetylase (HDAC) inhibition. SW480 cells with lower HDAC3 expression appeared to be poised for gene expression responses with increased histone H4-K12 acetylation, but not K5, K8, or K16 acetylation. Even though p21 was readily activated in HT29 cells, HDAC3 siRNA nonetheless stimulated p21 expression in these cells to a greater degree than HDAC1 and HDAC2 siRNA. SW480 cells with lower HDAC3 levels displayed an enhanced cell cycle arrest and growth inhibition by butyrate, but without changes in apoptosis or sensitivity to chemotherapeutic agents. As reported for other colon cancer cell lines, butyrate induced the rapid downregulation of the secretory cell differentiation markers mucin 2 and intestinal trefoil factor in SW480 cells. Interestingly, selective HDAC3 inhibition was sufficient to downregulate these genes. Our data support a central role for HDAC3 in regulating the cell proliferation and differentiation of colon cancer cells and suggest a potential mechanism by which colon cancers may become resistant to luminal butyrate.
- 167Mariadason, J. M. Dissecting HDAC3-mediated tumor progression. Cancer Biol. Ther. 2008, 7, 1581– 1583, DOI: 10.4161/cbt.7.10.6863[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktL3M&md5=71131081bb89241d463248a28db442bbDissecting HDAC3-mediated tumor progressionMariadason, John M.Cancer Biology & Therapy (2008), 7 (10), 1581-1583CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)A review. The research of Godman et al. (2008) entitled, \"HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling\" is reviewed with commentary and refs. The authors provided new insight into mechanisms by which histone deacetylase (HDAC)3 facilitates growth and survival of colon cancer cells in vitro. They showed that approx. 50% of the sequences are similarly altered in response to 18-h histone deacetylase inhibitors (HDACi) treatment. They further showed that the silencing of HDAC3 results in increased expression of several components of the TGFβ and interferon signaling pathways and in the modulation of components of the Wnt signaling pathway. Addnl., their data revealed that both transient and stable knockdown of HDAC3 induces expression of VDR mRNA and protein, and importantly, confers sensitivity of SW480 cells to vitamin D-induced growth inhibition.
- 168Godman, C. A.; Joshi, R.; Tierney, B. R.; Greenspan, E.; Rasmussen, T. P.; Wang, H. W.; Shin, D. G.; Rosenberg, D. W.; Giardina, C. HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. Cancer Biol. Ther. 2008, 7, 1570– 1580, DOI: 10.4161/cbt.7.10.6561[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktLzF&md5=7c87537af734a508cb5f4714bf467fd4HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signalingGodman, Cassandra A.; Joshi, Rashmi; Tierney, Brendan R.; Greenspan, Emily; Rasmussen, Theodore P.; Wang, Hsin-wei; Shin, Dong-Guk; Rosenberg, Daniel W.; Giardina, CharlesCancer Biology & Therapy (2008), 7 (10), 1570-1580CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)Histone deacetylase 3 (HDAC3) is overexpressed in approx. half of all colon adenocarcinomas. We took an RNAi approach to det. how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APCMin tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both pos. and neg. effects obsd. However, long-term knockdown of HDAC3 suppressed β-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
- 169Liu, K. H.; Fu, J.; Zhou, N.; Yin, W.; Yang, Y. Y.; Ouyang, S. X.; Liang, Y. M. 1,25-Dihydroxyvitamin D3 prevents epithelial-mesenchymal transition of HMrSV5 human peritoneal mesothelial cells by inhibiting histone deacetylase 3 (HDAC3) and increasing vitamin D receptor (VDR) expression through the Wnt/β-Catenin signaling pathway. Med. Sci. Monit. 2019, 25, 5892– 5902, DOI: 10.12659/MSM.916313[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1ylsL0%253D&md5=f34d51bd4a5dec86dcb55651da029dda1,25-dihydroxyvitamin D3 prevents epithelialmesenchymal transition of HMrSV5 human peritoneal mesothelial cells by inhibiting histone deacetylase 3 (HDAC3) and increasing vitamin D receptor (VDR) expression through the Wnt/β-catenin signaling pathwayLiu, Kang-Han; Fu, Jia; Zhou, Nan; Yin, Wei; Yang, Yi-Ya; Ouyang, Sha-Xi; Liang, Yu-MeiMedical Science Monitor (2019), 25 (), 5892-5902CODEN: MSMOFR; ISSN:1643-3750. (International Scientific Information, Inc.)Background: Peritoneal dialysis is the most common treatment for end-stage renal disease. However, peritoneal fibrosis resulting from long-term peritoneal dialysis restricts peritoneal ultrafiltration. Previous studies have shown a role for 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3) in preventing fibrosis, but the potential mechanisms remain unknown. This study aimed to investigate the role of 1,25(OH)2 D3 in epithelial-mesenchymal transition (EMT) and the downstream signaling pathway in HMrSV5 human peritoneal mesothelial cells in vitro. Material/Methods: An in vitro cell model of peritoneal fibrosis was established using the HMrSV5 human peritoneal mesothelial cell line. High glucose and lipopolysaccharide (LPS) culture conditions, with or without 1,25(OH)2 D3, were used. Wnt agonist 1, a Wnt signaling pathway activator, was applied. Quant. real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the vitamin D receptor (VDR) and histone deacetylase 3 (HDAC3) gene and protein expression levels, β -catenin, and EMT-assocd. biomarkers. Results: High glucose plus LPS culture medium inhibited cell proliferation, induced cell apoptosis and promoted EMT in HMrSV5 cells, which was reversed by 1,25(OH)2 D3 by down-regulation of HDAC3 and upregulation of VDR. HDAC3 inhibited VDR gene expression. The expression of EMT-assocd. biomarkers was increased by Wnt agonist 1 and inhibited by 1,25(OH)2 D3. Conclusions: In HMrSV5 human peritoneal mesothelial cells, 1,25(OH)2 D3 reversed EMT by inhibiting the expression of HDAC3 and upregulating VDR gene expression via the Wnt/β-catenin signaling pathway.
- 170Bacon, T.; Seiler, C.; Wolny, M.; Hughes, R.; Watson, P.; Schwabe, J.; Grigg, R.; Peckham, M. Histone deacetylase 3 indirectly modulates tubulin acetylation. Biochem. J. 2015, 472, 367– 377, DOI: 10.1042/BJ20150660[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFGnsrnO&md5=1362a80cfda02865bda00b9f79b96a80Histone deacetylase 3 indirectly modulates tubulin acetylationBacon, Travis; Seiler, Caroline; Wolny, Marcin; Hughes, Ruth; Watson, Peter; Schwabe, John; Grigg, Ronald; Peckham, MichelleBiochemical Journal (2015), 472 (3), 367-377CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. Blocking HDAC3 activity using MI192, a compd. specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behavior of microtubules in live cells. The siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3-silencing mediator of retinoic and thyroid receptors (SMRT)-deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation.
- 171Villagra, A.; Sotomayor, E. M.; Seto, E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene 2010, 29, 157– 173, DOI: 10.1038/onc.2009.334[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlSqsLbI&md5=73bed9eb86b3d8c35e02ce73e99753b3Histone deacetylases and the immunological network: implications in cancer and inflammationVillagra, A.; Sotomayor, E. M.; Seto, E.Oncogene (2010), 29 (2), 157-173CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. The initiation, magnitude and duration of an immune response against antigens are a tightly regulated process involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is crit. for allowing efficient immune response against foreign antigens while preventing autoimmune attack against self-antigens. In recent years, much effort has been devoted to understanding immune evasion by cancer cells. Also, significant advances have been made in mechanistically understanding the role of pro- and anti-inflammatory cytokines in the regulation of immune responses against antigens, including those expressed by tumors. However, the authors still know very little about the regulation of inflammatory/anti-inflammatory genes in their natural setting, the chromatin substrate. Several mechanisms have been identified to influence chromatin flexibility and allow dynamic changes in gene expression. Among those, chromatin modifications induced by acetylation and deacetylation of histone tails have gained wide attention. In this study, the authors discuss the role of histone deacetylases in the transcriptional regulation of genes involved in the inflammatory response and how these enzymes coordinate the dynamic expression of these genes during an immune response. This emerging knowledge is opening new avenues to better understand epigenetic regulation of inflammatory responses and providing new mol. targets for either amplifying or ameliorating immune responses.
- 172Zhang, Y.; Tuzova, M.; Xiao, Z. X.; Cruikshank, W. W.; Center, D. M. Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP. J. Immunol. 2008, 180, 402– 408, DOI: 10.4049/jimmunol.180.1.402[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjlvVChsA%253D%253D&md5=c94adad4f3ad436057bc31fd643388fdPro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABPZhang Yujun; Tuzova Marina; Xiao Zhi-Xiong J; Cruikshank William W; Center David MJournal of immunology (Baltimore, Md. : 1950) (2008), 180 (1), 402-8 ISSN:0022-1767.Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished in close correlation to the down-regulation of p27KIP1 protein. In addition, we showed that pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains elusive. In this study, we identified GA binding protein beta1 subunit (GABPbeta1) and histone deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPbeta1 and HDAC3 have canonical PDZ-binding motifs and specifically bind to the first and second PDZ domain of pro-IL-16, respectively. Heat shock cognate protein 70 (HSC70) also copurified with the GST-PDZ1-containing fragment but lacks a C-terminal PDZ binding motif, suggesting that it binds through a different mechanism. We further showed that pro-IL-16 is located in a GABP transcriptional complex bound to the Skp2 promoter. In addition, we demonstrated that HDAC activity is critical for pro-IL-16-induced cell cycle arrest. Taken altogether, these data suggest that pro-IL-16 forms a complex with GABPbeta1 and HDAC3 in suppressing the transcription of Skp2. Thus, this study has revealed a novel mechanism with which pro-IL-16 regulates T cell growth through the Skp2-p27KIP1 pathway.
- 173Ozawa, Y.; Towatari, M.; Tsuzuki, S.; Hayakawa, F.; Maeda, T.; Miyata, Y.; Tanimoto, M.; Saito, H. Histone deacetylase 3 associates with and represses the transcription factor GATA-2. Blood 2001, 98, 2116– 2123, DOI: 10.1182/blood.V98.7.2116[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsVChtr4%253D&md5=243533275b3caf737f571c73081070a2Histone deacetylase 3 associates with and represses the transcription factor GATA-2Ozawa, Yukiyasu; Towatari, Masayuki; Tsuzuki, Shinobu; Hayakawa, Fumihiko; Maeda, Takahiro; Miyata, Yasuhiko; Tanimoto, Mitsune; Saito, HidehikoBlood (2001), 98 (7), 2116-2123CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)The zinc finger transcription factor GATA-2 plays a crit. role in the survival and proliferation of hematopoietic stem cells. This study examd. the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly assocs. with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2-dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly assocd. with HDAC5 but not with other class II HDACs examd., i.e., HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members.
- 174Kumar, M. S.; Hancock, D. C.; Molina-Arcas, M.; Steckel, M.; East, P.; Diefenbacher, M.; Armenteros-Monterroso, E.; Lassailly, F.; Matthews, N.; Nye, E.; Stamp, G.; Behrens, A.; Downward, J. GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 2012, 149, 642– 655, DOI: 10.1016/j.cell.2012.02.059[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1Kjs7c%253D&md5=da14f8854da4b616c3d6e161364fabb9The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancerKumar, Madhu S.; Hancock, David C.; Molina-Arcas, Miriam; Steckel, Michael; East, Phillip; Diefenbacher, Markus; Armenteros-Monterroso, Elena; Lassailly, Francois; Matthews, Nik; Nye, Emma; Stamp, Gordon; Behrens, Axel; Downward, JulianCell (Cambridge, MA, United States) (2012), 149 (3), 642-655CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clin. approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation.
- 175Krämer, O. H.; Knauer, S. K.; Greiner, G.; Jandt, E.; Reichardt, S.; Gührs, K. H.; Stauber, R. H.; Böhmer, F. D.; Heinzel, T. A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev. 2009, 23, 223– 235, DOI: 10.1101/gad.479209[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FpvVOrtg%253D%253D&md5=6dca44d82ad68948ceab4b2957c223bbA phosphorylation-acetylation switch regulates STAT1 signalingKramer Oliver H; Knauer Shirley K; Greiner Georg; Jandt Enrico; Reichardt Sigrid; Guhrs Karl-Heinz; Stauber Roland H; Bohmer Frank D; Heinzel ThorstenGenes & development (2009), 23 (2), 223-35 ISSN:.Cytokines such as interferons (IFNs) activate signal transducers and activators of transcription (STATs) via phosphorylation. Histone deacetylases (HDACs) and the histone acetyltransferase (HAT) CBP dynamically regulate STAT1 acetylation. Here we show that acetylation of STAT1 counteracts IFN-induced STAT1 phosphorylation, nuclear translocation, DNA binding, and target gene expression. Biochemical and genetic experiments altering the HAT/HDAC activity ratio and STAT1 mutants reveal that a phospho-acetyl switch regulates STAT1 signaling via CBP, HDAC3, and the T-cell protein tyrosine phosphatase (TCP45). Strikingly, inhibition of STAT1 signaling via CBP-mediated acetylation is distinct from the functions of this HAT in transcriptional activation. STAT1 acetylation induces binding of TCP45, which catalyzes dephosphorylation and latency of STAT1. Our results provide a deeper understanding of the modulation of STAT1 activity. These findings reveal a new layer of physiologically relevant STAT1 regulation and suggest that a previously unidentified balance between phosphorylation and acetylation affects cytokine signaling.
- 176Hanigan, T. W.; Aboukhatwa, S. M.; Taha, T. Y.; Frasor, J.; Petukhov, P. A. Divergent JNK phosphorylation of HDAC3 in triple-negative breast cancer cells determines HDAC inhibitor binding and selectivity. Cell Chem. Biol. 2017, 24, 1356– 1367, DOI: 10.1016/j.chembiol.2017.08.015[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGnsrfF&md5=f63d68cc73cf1175890f39b6a91301bcDivergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and SelectivityHanigan, Thomas W.; Aboukhatwa, Shaimaa M.; Taha, Taha Y.; Frasor, Jonna; Petukhov, Pavel A.Cell Chemical Biology (2017), 24 (11), 1356-1367.e8CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACis) is unclear. In this study, we developed a method that identified a 3- to 16-fold increase in HDACi selectivity for HDAC3 in triple-neg. breast cancer (TNBC) cells in comparison with luminal subtypes that was not predicted by current practice measurements with recombinant proteins. We found this increase was caused by c-Jun N-terminal kinase (JNK) phosphorylation of HDAC3, was independent of HDAC3 complex compn. or subcellular localization, and was assocd. with a 5-fold increase in HDAC3 enzymic activity. This study points to HDAC3 and the JNK axes as targets in TNBC, highlights how HDAC phosphorylation affects HDACi binding and selectivity, and outlines a method to identify changes in individual HDAC isoforms catalytic activity, applicable to any disease state.
- 177Oie, S.; Matsuzaki, K.; Yokoyama, W.; Murayama, A.; Yanagisawa, J. HDAC3 regulates stability of estrogen receptor α mRNA. Biochem. Biophys. Res. Commun. 2013, 432, 236– 241, DOI: 10.1016/j.bbrc.2013.02.007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFWhsrk%253D&md5=e5cd396c2f8c4ed919ce69d4dbe3e4c0HDAC3 regulates stability of estrogen receptor α mRNAOie, Shohei; Matsuzaki, Kazuya; Yokoyama, Wataru; Murayama, Akiko; Yanagisawa, JunnBiochemical and Biophysical Research Communications (2013), 432 (2), 236-241CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Estrogen receptor alpha (ERα) expression is a risk factor for breast cancer. HDAC inhibitors have been demonstrated to down-regulate ERα expression in ERα-pos. breast cancer cell lines, but the mol. mechanisms are poorly understood.Here, we showed that HDAC inhibitors decrease the stability of ERα mRNA, and that knockdown of HDAC3 decreases the stability of ERα mRNA and suppresses estrogen-dependent proliferation of ERα-pos. MCF-7 breast cancer cells. In the Oncomine database, expression levels of HDAC3 in ERα-pos. tumors are higher than those in ERα-neg. tumors, thus suggesting that HDAC3 is necessary for ERα mRNA stability, and is involved in the estrogen-dependent proliferation of ERα-pos. tumors.
- 178Cui, Z.; Xie, M.; Wu, Z.; Shi, Y. Relationship between histone deacetylase 3 (HDAC3) and breast cancer. Med. Sci. Monit. 2018, 24, 2456– 2464, DOI: 10.12659/MSM.906576[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVGjtLfJ&md5=ee400af1bc4c2e2dbce592fed4b6b9dfRelationship between histone deacetylase 3 (HDAC3) and breast cancerCui, Zhuhong; Xie, Mingjun; Wu, Zhenru; Shi, YujunMedical Science Monitor (2018), 24 (), 2456-2464CODEN: MSMOFR; ISSN:1643-3750. (International Scientific Information, Inc.)Background: The modification of histone acetylation and deacetylation is the most important mechanism of chromatin re- modeling. These modifications are a subset of epigenetic alterations which affect tumorigenesis and progression through changes in gene expression and cell growth. Results of histone modification studies prompted us to explore the therapeutic and prognostic significance of histone deacetylase 3 (HDAC3) expression in patients with breast cancer. Material/Methods: Immunohistochem. (IHC) staining was used to detect HDAC3 expression in a tissue microarray (TMA) that included 145 patients diagnosed with invasive ductal breast carcinoma. IHC scoring was used to evaluate the staining intensity and the proportion of pos. cells. Results: HDAC3 expression was significantly correlated with estrogen receptor (ER)-neg. expression P=0.036) and progesterone receptor (PR)-neg. expression P=0.024). Addnl., HDAC3 expression was significantly pos. correlated with human epidermal growth factor 2 (HER2) overexpression P=0.037. Our study also indicated that high expression of HDAC3 was more frequently obsd. in breast tumors with PT2 classification (74%) vs. PT1 (50.0%) and PT3 (71.4%) P=0.040. Furthermore, HDAC3 was correlated with clin. stage II P=0.046. Univariate and multivariate survival analyses showed that high expression of HDAC3 was correlated with poor overall survival (OS) P=0.029 and P=0.033, resp. in patients without lymph node involvement. Conclusions: High HDAC3 expression is closely correlated with ER-neg. expression, PR-neg. expression, HER2 over-expression, PT stage, and clin. stage of breast tumors. HDAC3 may be an appropriate prognostic indicator in patients with invasive ductal breast cancer.
- 179Kim, H. C.; Choi, K. C.; Choi, H. K.; Kang, H. B.; Kim, M. J.; Lee, Y. H.; Lee, O. H.; Lee, J.; Kim, Y. J.; Jun, W.; Jeong, J. W.; Yoon, H. G. HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cells. Cell. Mol. Life Sci. 2010, 67, 3499– 3510, DOI: 10.1007/s00018-010-0388-5[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOrtb%252FJ&md5=98c63a68c8474d1c9cc622ae6faa85e0HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cellsKim, Han-Cheon; Choi, Kyung-Chul; Choi, Hyo-Kyoung; Kang, Hee-Bum; Kim, Mi-Jeong; Lee, Yoo-Hyun; Lee, Ok-Hee; Lee, Jeongmin; Kim, Young Jun; Jun, Woojin; Jeong, Jae-Wook; Yoon, Ho-GeunCellular and Molecular Life Sciences (2010), 67 (20), 3499-3510CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)We identified CREB3 as a novel HDAC3-interacting protein in a yeast two-hybrid screen for HDAC3-interacting proteins. Among all class I HDACs, CREB3 specifically interacts with HDAC3, in vitro and in vivo. HDAC3 efficiently inhibited CREB3-enhanced NF-κB activation, whereas the other class I HDACs did not alter NF-κB-dependent promoter activities or the expression of NF-κB target genes. Importantly, both knock-down of CREB3 and overexpression of HDAC3 suppressed the transcriptional activation of the novel CREB3-regulated gene, CXCR4. Furthermore, CREB3 was shown to bind to the CRE element in the CXCR4 promoter and to activate the transcription of the CXCR4 gene by causing dissocn. of HDAC3 and subsequently increasing histone acetylation. Importantly, both the depletion of HDAC3 and the overexpression of CREB3 substantially increased the migration of MDA-MB-231 metastatic breast cancer cells. Taken together, these findings suggest that HDAC3 selectively represses CREB3-mediated transcriptional activation and chemotactic signalling in human metastatic breast cancer cells.
- 180Hu, G.; He, N.; Cai, C.; Cai, F.; Fan, P.; Zheng, Z.; Jin, X. HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology 2019, 19, 383– 389, DOI: 10.1016/j.pan.2019.01.011[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVegs7g%253D&md5=31dc9dae3f2175097134f6d08c7b57b9HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancerHu, Guofu; He, Nan; Cai, Chuanqi; Cai, Fei; Fan, Ping; Zheng, Zhikun; Jin, XinPancreatology (2019), 19 (2), 383-389CODEN: PANCC2; ISSN:1424-3903. (Elsevier B.V.)Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy. Here, we reported that the specific inhibitor of histone deacetylase 3 (HDAC3) decreased the protein and mRNA level of PD-L1 in pancreatic cancer cells. Furthermore, we showed that HDAC3 was crit. for PD-L1 regulation and pos. correlated with PD-L1 in PDAC patient specimens. Finally, we demonstrated that HDAC3/signal transducer and activator of transcription 3 (STAT3) pathway transcriptionally regulated PD-L1 expression. Collectively, our data contributes to a better understanding of the function of HDAC3 in cancer immunity and the regulatory mechanism of PD-L1. More importantly, these data suggest that the HDAC3 inhibitors might be used to improve immunotherapy in pancreatic cancer.
- 181Liu, X.; Wang, J. H.; Li, S.; Li, L. L.; Huang, M.; Zhang, Y. H.; Liu, Y.; Yang, Y. T.; Ding, R.; Ke, Y. Q. Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase/ERK-MMP-laminin5γ2 signaling pathway. Cancer Sci. 2015, 106, 857– 866, DOI: 10.1111/cas.12684[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWqtrnE&md5=298f49a02006fde84f98f6b797018c13Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase / ERK-MMP-laminin5γ2 signaling pathwayLiu, Xiao; Wang, Ji-Hui; Li, Shun; Li, Lin-Lin; Huang, Min; Zhang, Yong-Hong; Liu, Yang; Yang, Yuan-Tao; Ding, Rui; Ke, Yi-QuanCancer Science (2015), 106 (7), 857-866CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)Vasculogenic mimicry (VM) refers to the process by which highly aggressive tumor cells mimic endothelial cells to form vessel-like structures that aid in supplying enough nutrients to rapidly growing tumors. Histone deacetylases (HDACs) regulate the expression and activity of numerous mols. involved in cancer initiation and progression. Notably, HDAC3 is overexpressed in the majority of carcinomas. However, thus far, no data are available to support the role of HDAC3 in VM. In this study, we subjected glioma specimens to immunohistochem. and histochem. double-staining methods and found that VM and HDAC3 expression were related to the pathol. grade of gliomas. The presence of VM correlated with HDAC3 expression in glioma tissues. The formation of tubular structures, as detd. by the tube formation assay to evaluate VM, was impaired in U87MG cells when transfected by siRNA or treated with an HDAC3 inhibitor. Importantly, the expression of VM-related mols. such as MMP-2/14 and laminin5γ2 was also affected when HDAC3 expression was altered. Furthermore, U87MG cells were treated with a phosphoinositide 3-kinase (PI3K) inhibitor or/and ERK inhibitor and found that the PI3K and ERK signaling pathways play key roles in VM; whereas, in VM, the two signaling pathways did not act upstream or downstream from each other. Taken together, our findings showed that HDAC3 contributed to VM in gliomas, possibly through the PI3K/ERK-MMPs-laminin5γ2 signaling pathway, which could potentially be a novel therapeutic target for gliomas.
- 182Zhang, B.; Liu, B.; Chen, D.; Setroikromo, R.; Haisma, H. J.; Quax, W. J. Histone deacetylase inhibitors sensitize TRAIL-induced apoptosis in colon cancer cells. Cancers 2019, 11, 645, DOI: 10.3390/cancers11050645[Crossref], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitV2mt7s%253D&md5=cf3fcfbc36d7d22cc7d49f27c46cd8ebHistone deacetylase inhibitors sensitize TRAIL-induced apoptosis in colon cancer cellsZhang, Baojie; Liu, Bin; Chen, Deng; Setroikromo, Rita; Haisma, Hidde J.; Quax, Wim J.Cancers (2019), 11 (5), 645CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi's), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi's, however, show considerable toxicity constraining clin. use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi's. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi's on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We obsd. that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.
- 183McLeod, A. B.; Stice, J. P.; Wardell, S. E.; Alley, H. M.; Chang, C. Y.; McDonnell, D. P. Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer. Prostate 2018, 78, 266– 277, DOI: 10.1002/pros.23467[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSjsrs%253D&md5=c188c27b16014c50d9e42783141a66a0Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancerMcLeod, Abigail B.; Stice, James P.; Wardell, Suzanne E.; Alley, Holly M.; Chang, Ching-yi; McDonnell, Donald P.Prostate (Hoboken, NJ, United States) (2018), 78 (4), 266-277CODEN: PRSTDS; ISSN:0270-4137. (Wiley-Blackwell)Background : Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclin. data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clin. studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date. Methods : The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA)-mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3-selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model. Results : Using genetic and pharmacol. approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also detd. that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein. Conclusions : Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC.
- 184Zhang, L.; Chen, Y.; Jiang, Q.; Song, W.; Zhang, L. Therapeutic potential of selective histone deacetylase 3 inhibition. Eur. J. Med. Chem. 2019, 162, 534– 542, DOI: 10.1016/j.ejmech.2018.10.072[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit12ltLrF&md5=fa992fb99f58bda9baddc1eaaf2d25e4Therapeutic potential of selective histone deacetylase 3 inhibitionZhang, Lihui; Chen, Yiming; Jiang, Qixiao; Song, Weiguo; Zhang, LeiEuropean Journal of Medicinal Chemistry (2019), 162 (), 534-542CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Histone deacetylases (HDACs) are closely related to the occurrence and development of a variety of diseases, such as tumor, inflammation, diabetes mellitus, cardiovascular and neurodegenerative diseases. Inhibition of HDACs by developing HDAC inhibitors has achieved significant progress in the treatment of diseases caused by epigenetic abnormalities, and esp. in the cancer therapy. Isoform selective HDAC inhibitors are emphasized to be disease specific and have less off-target effects and better safety performances. HDAC3 has been illustrated to play specific role in the development of several diseases, and the discovery of HDAC3 selective inhibitors has exhibited potential in the targeted disease treatment. Herein, we summarize the current knowledge about the prospects of selective inhibition of HDAC3 for the drug development.
- 185Zhao, N.; Li, S. W.; Wang, R. Z.; Xiao, M. H.; Meng, Y.; Zeng, C. X.; Fang, J. H.; Yang, J. E.; Zhuang, S. M. Expression of microRNA-195 is transactivated by Sp1 but inhibited by histone deacetylase 3 in hepatocellular carcinoma cells. Biochim. Biophys. Acta, Gene Regul. Mech. 2016, 1859, 933– 942, DOI: 10.1016/j.bbagrm.2016.05.006[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnvFOis7o%253D&md5=3e1ac1bfafee6067140a18ab1948c84eExpression of microRNA-195 is transactivated by Sp1 but inhibited by histone deacetylase 3 in hepatocellular carcinoma cellsZhao, Na; Li, Siwen; Wang, Ruizhi; Xiao, Manhuan; Meng, Yu; Zeng, Chunxian; Fang, Jian-Hong; Yang, Jine; Zhuang, Shi-MeiBiochimica et Biophysica Acta, Gene Regulatory Mechanisms (2016), 1859 (7), 933-942CODEN: BBAGC6; ISSN:1874-9399. (Elsevier B.V.)MiR-195 expression is frequently reduced in various cancers, but its underlying mechanisms remain unknown. To explore whether abnormal transcription contributed to miR-195 downregulation in hepatocellular carcinoma (HCC), we characterized the -2165-bp site upstream of mature miR-195 as transcription start site and the -2.4 to -2.0-kb fragment as the promoter of miR-195 gene. Subsequent investigation showed that deletion of the predicted Sp1 binding site decreased the miR-195 promoter activity; Sp1 silencing significantly reduced the miR-195 promoter activity and the endogenous miR-195 level; Sp1 directly interacted with the miR-195 promoter in vitro and in vivo. These data suggest Sp1 as a transactivator for miR-195 transcription. Interestingly, miR-195 expression was also subjected to epigenetic regulation. Histone deacetylase 3 (HDAC3) could anchor to the miR-195 promoter via interacting with Sp1 and consequently repress the Sp1-mediated miR-195 transactivation by deacetylating histone in HCC cells. Consistently, substantial increase of HDAC3 protein was detected in human HCC tissues and HDAC3 upregulation was significantly correlated with miR-195 downregulation, suggesting that HDAC3 elevation may represent an important cause for miR-195 redn. in HCC. Our findings uncover the mechanisms underlying the transcriptional regulation and expression deregulation of miR-195 in HCC cells and provide new insight into microRNA biogenesis in cancer cells.
- 186Xu, G. R.; Zhu, H. X.; Zhang, M. H.; Xu, J. H. Histone deacetylase 3 is associated with gastric cancer cell growth via the miR-454-mediated targeting of CHD5. Int. J. Mol. Med. 2017, 41, 155– 163, DOI: 10.3892/ijmm.2017.3225
- 187Yin, Y.; Zhang, M.; Dorfman, R. G.; Li, Y.; Zhao, Z.; Pan, Y.; Zhou, Q.; Huang, S.; Zhao, S.; Yao, Y.; Zou, X. Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition. Cell Death Dis. 2017, 8, e2856 DOI: 10.1038/cddis.2016.457[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCiur3L&md5=8928a846dd4ad5be1c224e2df90d82b0Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibitionYin, Yuyao; Zhang, Mingming; Dorfman, Robert Gregory; Li, Yang; Zhao, Zhenguo; Pan, Yida; Zhou, Qian; Huang, Shan; Zhao, Shimin; Yao, Yuling; Zou, XiaopingCell Death & Disease (2017), 8 (6), e2856CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochem. showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.
- 188Zhang, M.; Yin, Y.; Dorfman, R. G.; Zou, T.; Pan, Y.; Li, Y.; Wang, Y.; Zhou, Q.; Zhou, L.; Kong, B.; Friess, H.; Zhang, J.; Zhao, S.; Wang, L.; Zou, X. Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis. Oncotarget 2017, 8, 99402– 99413, DOI: 10.18632/oncotarget.19660[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MzitVSksA%253D%253D&md5=142f57cbd288ee72476d0a4524640752Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosisZhang Mingming; Yin Yuyao; Li Yang; Wang Yuming; Zhou Lixing; Kong Bo; Wang Lei; Zou Xiaoping; Zhang Mingming; Zhao Shimin; Dorfman Robert G; Zou Tianhui; Pan Yida; Zhang Jun; Zhao Shimin; Zhou Qian; Zhao Shimin; Kong Bo; Friess HelmutOncotarget (2017), 8 (59), 99402-99413 ISSN:.Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA .
- 189Wells, C. E.; Bhaskara, S.; Stengel, K. R.; Zhao, Y.; Sirbu, B.; Chagot, B.; Cortez, D.; Khabele, D.; Chazin, W. J.; Cooper, A.; Jacques, V.; Rusche, J.; Eischen, C. M.; McGirt, L. Y.; Hiebert, S. W. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One 2013, 8, e68915 DOI: 10.1371/journal.pone.0068915[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1aisrrK&md5=5bbf6c64dd030d2a370d198589079903Inhibition of Histone deacetylase 3 causes replication stress in cutaneous T cell lymphomaWells, Christina E.; Bhaskara, Srividya; Stengel, Kristy R.; Zhao, Yue; Sirbu, Bianca; Chagot, Benjamin; Cortez, David; Khabele, Dineo; Chazin, Walter J.; Cooper, Andrew; Jacques, Vincent; Rusche, James; Eischen, Christine M.; McGirt, Laura Y.; Hiebert, Scott W.PLoS One (2013), 8 (7), e68915CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metab., and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was assocd. with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was assocd. with chromatin and is present at and around DNA replication forks. DNA fiber labeling anal. showed that inhibition of HDAC3 resulted in a significant redn. in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death.
- 190Gupta, M.; Han, J. J.; Stenson, M.; Wellik, L.; Witzig, T. E. Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy. Leukemia 2012, 26, 1356– 1364, DOI: 10.1038/leu.2011.340[Crossref], [PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot1emt74%253D&md5=639b2827411ad5b4c3ba31c16568b961Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapyGupta, M.; Han, J. J.; Stenson, M.; Wellik, L.; Witzig, T. E.Leukemia (2012), 26 (6), 1356-1364CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-pos. DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3Tyr705 phosphorylation with minimal effect on STAT3Ser727 and JAK2 tyrosine activity. pSTAT3Tyr705-pos. DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3Tyr705-neg. DLBCLs. This cytotoxicity was assocd. with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation and inhibited survival of pSTAT3-pos. DLBCL cells. These studies provide the rationale for targeting STAT3-pos. DLBCL tumors with HDAC inhibitors.
- 191Narita, N.; Fujieda, S.; Tokuriki, M.; Takahashi, N.; Tsuzuki, H.; Ohtsubo, T.; Matsumoto, H. Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer. Oncogene 2005, 24, 7346– 7354, DOI: 10.1038/sj.onc.1208879[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtF2ns7%252FI&md5=c3046947f2fc5b18ef1ae1142e1f24e4Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancerNarita, Norihiko; Fujieda, Shigeharu; Tokuriki, Masaharu; Takahashi, Noboru; Tsuzuki, Hideaki; Ohtsubo, Toshio; Matsumoto, HidekiOncogene (2005), 24 (49), 7346-7354CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)To elucidate the mol. mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 44° for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 44° for 30 min at pH 6.7. Although the cytotoxicity of heating at 44° for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G2/M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G2/M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43° for 30 min in vivo. Analyses of p65 activity suggested that NF-κB is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.
- 192Ho, M.; Chen, T.; Liu, J.; Dowling, P.; Hideshima, T.; Zhang, L.; Morelli, E.; Camci-Unal, G.; Wu, X.; Tai, Y. T.; Wen, K.; Samur, M.; Schlossman, R. L.; Mazitschek, R.; Kavanagh, E. L.; Lindsay, S.; Harada, T.; McCann, A.; Anderson, K. C.; O’Gorman, P.; Bianchi, G. Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia 2020, 34, 196– 209, DOI: 10.1038/s41375-019-0493-x[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVyqs7bE&md5=27482093e7a20546132cf4a18ab409d5Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signalingHo, Matthew; Chen, Tianzeng; Liu, Jiye; Dowling, Paul; Hideshima, Teru; Zhang, Li; Morelli, Eugenio; Camci-Unal, Gulden; Wu, Xinchen; Tai, Yu-Tzu; Wen, Kenneth; Samur, Mehmet; Schlossman, Robert L.; Mazitschek, Ralph; Kavanagh, Emma L.; Lindsay, Sinead; Harada, Takeshi; McCann, Amanda; Anderson, Kenneth C.; O'Gorman, Peter; Bianchi, GiadaLeukemia (2020), 34 (1), 196-209CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacol. inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quant. and qual. changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as mol. mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clin. development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment.
- 193Zhang, L.; Hong, Z.; Zhang, R. R.; Sun, X. Z.; Yuan, Y. F.; Hu, J.; Wang, X. Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways. Biomed. Pharmacother. 2016, 83, 958– 966, DOI: 10.1016/j.biopha.2016.07.049[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWmtrzJ&md5=42cfc771b7a353471bb349cbe1bc0767Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathwaysZhang, Lei; Hong, Ze; Zhang, Rong-rong; Sun, Xing-zhen; Yuan, Yu-fang; Hu, Jian; Wang, XiangBiomedicine & Pharmacotherapy (2016), 83 (), 958-966CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Leukemia has been the third type of cancer killing many people across the world. Bakkenolide A (Bak), extd. from Petasites tricholobus, has been suggested to against cancer and display protective effects on inflammatory cytokines formation. And increasing evidences suggest that histone deacetylase 3 (HDAC3) plays vital roles in cancer formation and persistence via cell death, apoptosis and inflammation. But the function of Bakkenolide A in regulating leukemia is not understood yet, particularly via HDAC3. Here, we found that HDAC3 is up-regulated in clin. samples of leukemia compared with adjacent normal tissues. Then the expression of HDAC3 was knocked down via RNA interference in K562 cells. And inhibition of HDAC3 expression is able to improve leukemia invasion, migration and proliferation. Further, we also found HDAC3 bound to IκBα, affecting subsequent inflammation response. Moreover, Bakkenolide A was found to inhibit inflammation, induce apoptosis and cell death in leukemia cells via PI3K-regulated signaling pathway, down-regulating IKKs expression and suppressing in proinflammatory cytokines of IL-1β, IL-18 and TNF-α. Up-regulation of Caspase3/7 was obsd. in cells of HDAC3-knockdown and Bakkenolide A treatment, inducing leukemia cell apoptosis. Also, the expression of Akt and GSK were activated by HDAC3-knockdown and Bakkenolide A-treatment. Thus, these results indicated that Bakkenolide A-mediated HDAC3 sensitization in leukemia cells seem to be assocd. with activation of effector IKKs, Akt/GSK, and caspases through induction of the PI3K pathway, leading to inflammation, cell death, and apoptosis.
- 194Yan, Y.; An, J.; Yang, Y.; Wu, D.; Bai, Y.; Cao, W.; Ma, L.; Chen, J.; Yu, Z.; He, Y.; Jin, X.; Pan, Y.; Ma, T.; Wang, S.; Hou, X.; Weroha, S. J.; Karnes, R. J.; Zhang, J.; Westendorf, J. J.; Wang, L.; Chen, Y.; Xu, W.; Zhu, R.; Wang, D.; Huang, H. Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Mol. Med. 2018, 10, e8478 DOI: 10.15252/emmm.201708478
- 195Xu, Y.; Voelter-Mahlknecht, S.; Mahlknecht, U. The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell lines. Int. J. Mol. Med. 2005, 15, 169– 172[PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFeiug%253D%253D&md5=b3d836b7b2cf1edb5c85a3aa43672c50The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell linesXu, Yaoxian; Voelter-Mahlknecht, Susanne; Mahlknecht, UlrichInternational Journal of Molecular Medicine (2005), 15 (1), 169-172CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)In chronic myelocytic leukemia (CML) the activity of the Bcr-Abl tyrosine kinase is known to activate a no. of mol. mechanisms,, which inhibit apoptosis. In the present study, we show that the histone deacetylase inhibitor SARA (suberoylanilide hydroxamic acid) markedly decreases protein expression levels of Bcr-Abl and c-Myc in BV-173 cells, while in K562 cells only a minor decrease of Bcr-Abl protein levels is obsd. while a considerable redn. of c-Myc protein expression may only be achieved at higher concns. of SAHA. In addn., we found BV-173 cells to be more sensitive to SAHA-induced apoptosis when compared to K562 cells. Even though earlier reports on SAHA considerably focused on its inhibitory effect on HDAC enzymic activity, we report herein a significant downregulation of HDAC3 protein expression levels following treatment with SAHA in BV-173 cells, but not in K562 cells. In conclusion, our results imply a mol. mechanism for SAHA-induced apoptosis in BV-173 cells, which involves decreased protein expression levels of Bcr-Abl, c-Myc and HDAC3.
- 196Harada, T.; Ohguchi, H.; Grondin, Y.; Kikuchi, S.; Sagawa, M.; Tai, Y. T.; Mazitschek, R.; Hideshima, T.; Anderson, K. C. HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 2017, 31, 2670– 2677, DOI: 10.1038/leu.2017.144[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCiurfJ&md5=1bd7e215aa417f78eb0b51ac0c482144HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implicationsHarada, T.; Ohguchi, H.; Grondin, Y.; Kikuchi, S.; Sagawa, M.; Tai, Y.-T.; Mazitschek, R.; Hideshima, T.; Anderson, K. C.Leukemia (2017), 31 (12), 2670-2677CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clin. efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clin. activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degrdn. of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), resp., triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
- 197Lombard, D. B.; Cierpicki, T.; Grembecka, J. Combined MAPK pathway and HDAC inhibition breaks melanoma. Cancer Discovery 2019, 9, 469– 471, DOI: 10.1158/2159-8290.CD-19-0069[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslKksLzP&md5=442f8bd62e83ea5968c9a4e503c6e9b2Combined MAPK pathway and HDAC inhibition breaks melanomaLombard, David B.; Cierpicki, Tomasz; Grembecka, JolantaCancer Discovery (2019), 9 (4), 469-471CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)A review. In this issue, Maertens and colleagues demonstrate that HDAC3 inhibition potentiates the effects of MAPK pathway inhibitors in melanoma, including difficult-to-treat NRAS- and NF1-driven tumors, with MGMT expression serving as a biomarker for responsiveness to the BRAF/MEK/HDAC inhibitor combination. Mechanistically, this triple cocktail suppresses expression of genes involved in DNA repair, leading to enhanced killing of melanoma cells.
- 198Escaffit, F.; Vaute, O.; Chevillard-Briet, M.; Segui, B.; Takami, Y.; Nakayama, T.; Trouche, D. Cleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progression. Mol. Cell. Biol. 2007, 27, 554– 567, DOI: 10.1128/MCB.00869-06[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvVOmuw%253D%253D&md5=577bb1dfd418ae9c06ec7760af1dc18bCleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progressionEscaffit, Fabrice; Vaute, Olivier; Chevillard-Briet, Martine; Segui, Bruno; Takami, Yasunari; Nakayama, Tatsuo; Trouche, DidierMolecular and Cellular Biology (2007), 27 (2), 554-567CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The histone deacetylase 3 (HDAC-3), which is a known corepressor of many proapoptotic genes, is subjected to proteolytic cleavage during apoptosis in a cell type- and species-independent manner. This cleavage is caspase dependent and leads to the loss of the C-terminal part of HDAC-3. The cleaved form of HDAC-3 accumulates in the cytoplasm. Furthermore, we found that forced nuclear localization of HDAC-3 decreases the efficiency of apoptosis induction, indicating that HDAC-3 cytoplasmic relocalization is important for the apoptotic process. Finally, we obsd. that HDAC-3 cleavage allowed increased histone acetylation and transcriptional activation on a proapoptotic HDAC-3-target gene, the Fas-encoding gene. Altogether, our results thus indicate that HDAC-3 cleavage is crucial for efficient apoptosis induction because it allows the activation of some proapoptotic genes during apoptosis progression.
- 199Xia, Y.; Wang, J.; Liu, T. J.; Yung, W. K.; Hunter, T.; Lu, Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol. Cell 2007, 25, 219– 232, DOI: 10.1016/j.molcel.2007.01.005[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhslKjurY%253D&md5=d162c146b04311b1e4e88e3dadf48561c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosisXia, Yan; Wang, Ji; Liu, Ta-Jen; Yung, W. K. Alfred; Hunter, Tony; Lu, ZhiminMolecular Cell (2007), 25 (2), 219-232CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)C-Jun, a major transcription factor in the activating protein 1 (AP-1) family of regulatory proteins, is activated by many physiol. and pathol. stimuli. However, whether c-jun is regulated by epigenetic modification of chromatin structure is not clear. We showed here that c-jun was transcriptionally repressed in response to osmotic stress via a truncated HDAC3 generated by caspase-7-dependent cleavage at aspartic acid 391. The activation of caspase-7, which is independent of cytochrome c release and activation of caspase-9 and caspase-12, depends on activation of caspase-8, which in turn requires MEK2 activity and secretion of FAS ligand. The cell apoptosis induced by the truncated HDAC3 or enhanced by c-Jun deficiency during osmotic stress was suppressed by exogenous expression of c-Jun, indicating that the downregulation of c-Jun by HDAC3-dependent transcriptional repression plays a role in regulating cell survival and apoptosis.
- 200He, P.; Li, K.; Li, S. B.; Hu, T. T.; Guan, M.; Sun, F. Y.; Liu, W. W. Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer. Int. J. Oncol. 2018, 52, 1305– 1316, DOI: 10.3892/ijo.2018.4284[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOqsLbL&md5=d072b6ca93d15bd16138b4efce99f6b7Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancerHe, Ping; Li, Ke; Li, Shi-Bao; Hu, Ting-Ting; Guan, Ming; Sun, Fen-Yong; Liu, Wei-WeiInternational Journal of Oncology (2018), 52 (4), 1305-1316CODEN: IJONES; ISSN:1791-2423. (Spandidos Publications Ltd.)A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent noncancerous tissues, as well as in SW480 cells were examd. by immunohistochem., RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examd. by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle anal. and Transwell assays. The results revealed that the redn. or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti-apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3.
- 201Ma, Y.; Baltezor, M.; Rajewski, L.; Crow, J.; Samuel, G.; Staggs, V. S.; Chastain, K. M.; Toretsky, J. A.; Weir, S. J.; Godwin, A. K. Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis. J. Mol. Med. (Heidelberg, Ger.) 2019, 97, 957– 962, DOI: 10.1007/s00109-019-01782-0[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXos12itbk%253D&md5=8c4c37d083b496d26a4df0a39317cd66Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axisMa, Yan; Baltezor, Michael; Rajewski, Lian; Crow, Jennifer; Samuel, Glenson; Staggs, Vincent S.; Chastain, Katherine M.; Toretsky, Jeffrey A.; Weir, Scott J.; Godwin, Andrew K.Journal of Molecular Medicine (Heidelberg, Germany) (2019), 97 (7), 957-972CODEN: JMLME8; ISSN:0946-2716. (Springer)Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 mo of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clin. benefit, thereby emphasizing a clin. responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclin. proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclin. ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, resp. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clin. development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. Entinostat potently inhibits ES both in vitro and in vivo. · EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. · Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. · HDAC3 is a transcriptional target of EWS-FLI1. · HDAC3 is essential for ES cell viability and genomic stability maintenance.
- 202Zeng, Z.; Liao, R.; Yao, Z.; Zhou, W.; Ye, P.; Zheng, X.; Li, X.; Huang, Y.; Chen, S.; Chen, Q. Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: a community-based case-control study. Gene 2014, 533, 427– 433, DOI: 10.1016/j.gene.2013.09.123[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yhsbzM&md5=842d6b57b0fdf499306d12d7ad456fe6Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: A community-based case-control studyZeng, Zhuanping; Liao, Rifang; Yao, Zhenjiang; Zhou, Weiping; Ye, Ping; Zheng, Xueyan; Li, Xing; Huang, Yanhui; Chen, Sidong; Chen, QingGene (2014), 533 (1), 427-433CODEN: GENED6; ISSN:0378-1119. (Elsevier B.V.)There are no data regarding the possible role of the single nucleotide polymorphism (SNP) of class I histone deacetylases (HDACs) in type 2 diabetes mellitus (DM). We designed this study to examine whether polymorphisms of HDACs can be implicated in that disease. A community-based, case-control study was conducted, with a total of 568 subjects (284 patients and 284 controls) enrolled. Four polymorphisms of HDAC1 (rs1741981) and HDAC3 (rs11741808, rs2547547, rs2530223) were examd. by the use of TaqMan technol. We found a significant assocn. with risk of type 2 DM for three SNPs of HDAC3, including rs11741808 [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.35-0.81], rs2547547 [OR = 1.72, 95% CI: 1.13-2.64], and rs2530223 [OR = 1.39; 95% CI: 1.01-1.91]. Subgroup anal. showed that BMI ≥ 23 kg/m2, high triglyceride and high blood pressure, together with the rs11741808AG genotype, were assocd. with a significantly decreased risk for type 2 DM, with ORs of 0.50 (95% CI: 0.27-0.91), 0.38 (95% CI: 0.20-0.71) and 0.43 (95% CI: 0.24-0.76) compared with the AA genotype, resp. In a population with normal total cholesterol, the AG genotype yielded a significantly decreased risk of type 2 DM risk, with an OR of 0.42 (95% CI: 0.25-0.70) when compared with the persons of the AA genotype. For rs2547547, in a population with normal total cholesterol and triglyceride, the AG genotype was assocd. with a significantly increased risk of type 2 DM, with ORs of 1.92 (95% CI: 1.17-3.15) and 2.24 (95% CI: 1.28-3.94) when compared with the population carrying the AA genotype. The results suggest that variants of HDAC3 contribute to an increased prevalence of type 2 DM in the Chinese Han population.
- 203Lundh, M.; Galbo, T.; Poulsen, S. S.; Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes, Obes. Metab. 2015, 17, 703– 707, DOI: 10.1111/dom.12470[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOnur3I&md5=ce9b1112670b4e3b07ffce66f1ba8b38Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic ratsLundh, M.; Galbo, T.; Poulsen, S. S.; Mandrup-Poulsen, T.Diabetes, Obesity and Metabolism (2015), 17 (7), 703-707CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)Failure of pancreatic β cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to β-cell failure. Selective inhibition of histone deacetylase (HDAC)-3 protects pancreatic β cells against inflammatory and metabolic insults in vitro. In the present study, we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycemia and increase insulin secretion in a rat model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycemic clamp was performed. HDAC3 inhibition improved hyperglycemia over the study period without affecting wt. gain. At the end of the hyperglycemic clamp, circulating insulin levels were significantly higher in BRD3308-treated rats. Pancreatic insulin staining and contents were also significantly higher. These findings highlight HDAC3 as a key therapeutic target for β-cell protection in type 2 diabetes.
- 204Wagner, F. F.; Lundh, M.; Kaya, T.; McCarren, P.; Zhang, Y. L.; Chattopadhyay, S.; Gale, J. P.; Galbo, T.; Fisher, S. L.; Meier, B. C.; Vetere, A.; Richardson, S.; Morgan, N. G.; Christensen, D. P.; Gilbert, T. J.; Hooker, J. M.; Leroy, M.; Walpita, D.; Mandrup-Poulsen, T.; Wagner, B. K.; Holson, E. B. An isochemogenic set of inhibitors to define the therapeutic potential of histone deacetylases in β-cell protection. ACS Chem. Biol. 2016, 11, 363– 374, DOI: 10.1021/acschembio.5b00640[ACS Full Text], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVCnsL4%253D&md5=0d57ffcfc229ec4efe3857882ff9113eAn Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell ProtectionWagner, Florence F.; Lundh, Morten; Kaya, Taner; McCarren, Patrick; Zhang, Yan-Ling; Chattopadhyay, Shrikanta; Gale, Jennifer P.; Galbo, Thomas; Fisher, Stewart L.; Meier, Bennett C.; Vetere, Amedeo; Richardson, Sarah; Morgan, Noel G.; Christensen, Dan Ploug; Gilbert, Tamara J.; Hooker, Jacob M.; Leroy, Melanie; Walpita, Deepika; Mandrup-Poulsen, Thomas; Wagner, Bridget K.; Holson, Edward B.ACS Chemical Biology (2016), 11 (2), 363-374CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-mol. inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clin. experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chem. matched inhibitors to probe the role of class I HDACs in β-cell pathobiol. and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biol. activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addn., BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.
- 205Ye, J. Improving insulin sensitivity with HDAC inhibitor. Diabetes 2013, 62, 685– 687, DOI: 10.2337/db12-1354[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGrt7g%253D&md5=001cf6dbd06237bdc3cee19f54aeb9baImproving insulin sensitivity with HDAC inhibitorYe, JianpingDiabetes (2013), 62 (3), 685-687CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)A review. The research of Galmozzi et al. (2013) entitled 'Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metab. in skeletal muscle and adipose tissue' is reviewed with commentary and refs. The study by these authors provides new insight into the distinction between class I and class II inhibitors in regulation of insulin sensitivity. Their results showed that class I histone deacetylase inhibitors (HDACi) enhanced whole-body energy expenditure, improved insulin sensitivity, and stimulated oxidative phosphorylation and mitochondrial function in the muscle and fat of mice. The mechanism was attributed to induction of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α. In contrast, class II HDACi did not exhibit these actions, suggesting that class I HDACi are more important in the regulation of energy metab. and insulin sensitivity. Despite these interesting new findings, these data should be interpreted with caution.
- 206Gao, Z.; He, Q.; Peng, B.; Chiao, P. J.; Ye, J. Regulation of nuclear translocation of HDAC3 by IkappaBalpha is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J. Biol. Chem. 2006, 281, 4540– 4547, DOI: 10.1074/jbc.M507784200[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlKrs78%253D&md5=6f143e89f1279e7846e3b02196f41bfdRegulation of Nuclear Translocation of HDAC3 by IκBα Is Required for Tumor Necrosis Factor Inhibition of Peroxisome Proliferator-activated Receptor γ FunctionGao, Zhanguo; He, Qing; Peng, Bailu; Chiao, Paul J.; Ye, JianpingJournal of Biological Chemistry (2006), 281 (7), 4540-4547CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Inhibition of peroxisome proliferator-activated receptor γ (PPARγ) function by TNF-α contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the mol. mechanism is not fully understood. In this study, the authors demonstrate that nuclear translocation of HDAC3 is regulated by TNF-α, and this event is required for inhibition of transcriptional activity of PPARγ by TNF-α. HDAC3 is assocd. with IκBα in the cytoplasm. After IκBα degrdn. in response to TNF-α, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of IκBα, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is assocd. with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPARγ by TNF-α is not assocd. with a redn. in the DNA binding activity of PPARγ. Rather, these results suggest that IκBα-dependent nuclear translocation of HDAC3 is responsible for PPARγ inhibition by TNF-α.
- 207Jiang, X.; Ye, X.; Guo, W.; Lu, H.; Gao, Z. Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J. Mol. Endocrinol. 2014, 53, 191– 200, DOI: 10.1530/JME-14-0066[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfotFGmsQ%253D%253D&md5=b60551a5092649169e960beaa3509ebbInhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylationJiang Xiaoting; Ye Xin; Guo Wei; Lu Hongyun; Gao ZhanguoJournal of molecular endocrinology (2014), 53 (2), 191-200 ISSN:.Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.
- 208Chou, D. H.; Holson, E. B.; Wagner, F. F.; Tang, A. J.; Maglathlin, R. L.; Lewis, T. A.; Schreiber, S. L.; Wagner, B. K. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem. Biol. 2012, 19, 669– 673, DOI: 10.1016/j.chembiol.2012.05.010[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVKrsL4%253D&md5=47153de783321575c2f5606f16d28bb8Inhibition of Histone Deacetylase 3 Protects Beta Cells from Cytokine-Induced ApoptosisChou, Danny Hung-Chieh; Holson, Edward B.; Wagner, Florence F.; Tang, Alicia J.; Maglathlin, Rebecca L.; Lewis, Timothy A.; Schreiber, Stuart L.; Wagner, Bridget K.Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 669-673CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Cytokine-induced beta-cell apoptosis is important to the etiol. of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compds. restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis.
- 209Xu, Z.; Tong, Q.; Zhang, Z.; Wang, S.; Zheng, Y.; Liu, Q.; Qian, L. B.; Chen, S. Y.; Sun, J.; Cai, L. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin. Sci. 2017, 131, 1841– 1857, DOI: 10.1042/CS20170064[Crossref], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Wrs73K&md5=686f184cf3ae5e901b6e7dfd35680eabInhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathwayXu, Zheng; Tong, Qian; Zhang, Zhiguo; Wang, Shudong; Zheng, Yang; Liu, Qiuju; Qian, Ling-bo; Chen, Shao-yu; Sun, Jian; Cai, LuClinical Science (2017), 131 (15), 1841-1857CODEN: CSCIAE; ISSN:1470-8736. (Portland Press Ltd.)Inhibition of total histone deacetylases (HDACs) was phenomenally assocd. with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to det. whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevents DCM. Type 1 diabetes OVE26 and age-matched wild-type (WT) mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 mo. These mice were then killed immediately or 3 mo later for cardiac function and pathol. examn. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice killed immediately or 3 mo later following the 3-mo treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunopptn. (ChIP) assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. The present study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.
- 210Dávalos-Salas, M.; Montgomery, M. K.; Reehorst, C. M.; Nightingale, R.; Ng, I.; Anderton, H.; Al-Obaidi, S.; Lesmana, A.; Scott, C. M.; Ioannidis, P.; Kalra, H.; Keerthikumar, S.; Tögel, L.; Rigopoulos, A.; Gong, S. J.; Williams, D. S.; Yoganantharaja, P.; Bell-Anderson, K.; Mathivanan, S.; Gibert, Y.; Hiebert, S.; Scott, A. M.; Watt, M. J.; Mariadason, J. M. Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity. Nat. Commun. 2019, 10, 5219, DOI: 10.1038/s41467-019-13180-8
- 211Knutson, S. K.; Chyla, B. J.; Amann, J. M.; Bhaskara, S.; Huppert, S. S.; Hiebert, S. W. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 2008, 27, 1017– 1028, DOI: 10.1038/emboj.2008.51[Crossref], [PubMed], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXksVagurs%253D&md5=eefeb4f059e6cbbbb176d8d8c3d93462Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networksKnutson, Sarah K.; Chyla, Brenda J.; Amann, Joseph M.; Bhaskara, Srividya; Huppert, Stacey S.; Hiebert, Scott W.EMBO Journal (2008), 27 (7), 1017-1028CODEN: EMJODG; ISSN:0261-4189. (Nature Publishing Group)Histone deacetylase 3 (Hdac3) is an enzymic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of Hdac3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ line of mice caused embryonic lethality. Therefore, we deleted Hdac3 in the postnatal mouse liver. These mice developed hepatomegaly, which was the result of hepatocyte hypertrophy, and these morphol. changes coincided with significant imbalances between carbohydrate and lipid metab. Loss of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Loss of Hdac3 also increased the levels of Pparγ2, and treatment of these mice with a Pparγ antagonist partially reversed the lipid accumulation in the liver. In addn., gene expression anal. identified mammalian target of rapamycin signaling as being activated after deletion of Hdac3, and inhibition by rapamycin affected the accumulation of neutral lipids in Hdac3-null livers. Thus, Hdac3 regulates metab. through multiple signaling pathways in the liver, and deletion of Hdac3 disrupts normal metabolic homeostasis.
- 212Sun, Z.; Miller, R. A.; Patel, R. T.; Chen, J.; Dhir, R.; Wang, H.; Zhang, D.; Graham, M. J.; Unterman, T. G.; Shulman, G. I.; Sztalryd, C.; Bennett, M. J.; Ahima, R. S.; Birnbaum, M. J.; Lazar, M. A. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 2012, 18, 934– 942, DOI: 10.1038/nm.2744[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFOqsLw%253D&md5=30f561509e16f7550ec6ff0acd264654Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestrationSun, Zheng; Miller, Russell A.; Patel, Rajesh T.; Chen, Jie; Dhir, Ravindra; Wang, Hong; Zhang, Dongyan; Graham, Mark J.; Unterman, Terry G.; Shulman, Gerald I.; Sztalryd, Carole; Bennett, Michael J.; Ahima, Rexford S.; Birnbaum, Morris J.; Lazar, Mitchell A.Nature Medicine (New York, NY, United States) (2012), 18 (6), 934-942CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Fatty liver disease is assocd. with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body wt. compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose prodn. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2-coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metab.
- 213Sun, Z.; Singh, N.; Mullican, S. E.; Everett, L. J.; Li, L.; Yuan, L.; Liu, X.; Epstein, J. A.; Lazar, M. A. Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J. Biol. Chem. 2011, 286, 33301– 33309, DOI: 10.1074/jbc.M111.277707[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOit7rP&md5=7b56dc884e4d811ba06e8ccb51f28363Diet-induced Lethality Due to Deletion of the Hdac3 Gene in Heart and Skeletal MuscleSun, Zheng; Singh, Nikhil; Mullican, Shannon E.; Everett, Logan J.; Li, Li; Yuan, Li-Jun; Liu, Xi; Epstein, Jonathan A.; Lazar, Mitchell A.Journal of Biological Chemistry (2011), 286 (38), 33301-33309, S33301/1-S33301/47CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Many human diseases result from the influence of the nutritional environment on gene expression. The environment interacts with the genome by altering the epigenome, including covalent modification of nucleosomal histones. Here, we report a novel and dramatic influence of diet on the phenotype and survival of mice in which histone deacetylase 3 (Hdac3) is deleted postnatally in heart and skeletal muscle. Although embryonic deletion of myocardial Hdac3 causes major cardiomyopathy that reduces survival, we found that excision of Hdac3 in heart and muscle later in development leads to a much milder phenotype and does not reduce survival when mice are fed normal chow. Remarkably, upon switching to a high fat diet, the mice begin to die within weeks and display signs of severe hypertrophic cardiomyopathy and heart failure. Down-regulation of myocardial mitochondrial bioenergetic genes, specifically those involved in lipid metab., precedes the full development of cardiomyopathy, suggesting that HDAC3 is important in maintaining proper mitochondrial function. These data suggest that loss of the epigenomic modifier HDAC3 causes dietary lethality by compromising the ability of cardiac mitochondria to respond to changes of nutritional environment. In addn., this study provides a mouse model for diet-inducible heart failure.
- 214Moumné, L.; Campbell, K.; Howland, D.; Ouyang, Y.; Bates, G. P. Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington’s disease. PLoS One 2012, 7, e31080 DOI: 10.1371/journal.pone.0031080[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVWiu7Y%253D&md5=c3cd65445b80fe8610c85ccd2503b88fGenetic knock-down of Hdac3 does not modify disease-related phenotypes in a mouse model of Huntington's diseaseMoumne, Lara; Campbell, Ken; Howland, David; Ouyang, Yingbin; Bates, Gillian P.PLoS One (2012), 7 (2), e31080CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissoc. the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s) involved in this process. For this purpose, we are exploring the effect of the genetic redn. of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic redn. in R6/2, we generated a mouse carrying a crit. deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3+/- heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiol. or behavioral phenotypes and has no effect on mol. changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.
- 215Zhang, J.; Henagan, T. M.; Gao, Z.; Ye, J. Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammation. Endocrinology 2011, 152, 1829– 1838, DOI: 10.1210/en.2010-0828[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVKqurk%253D&md5=b4a96a10328828168b2cb07f92a372e5Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammationZhang, Jin; Henagan, Tara M.; Gao, Zhanguo; Ye, JianpingEndocrinology (2011), 152 (5), 1829-1838CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)We have reported that the nuclear factor-κB (NF-κB) induces chronic inflammation in the adipose tissue of p65 transgenic (Tg) mice, in which the NF-κB subunit p65 (RelA) is overexpressed from the adipocyte protein 2 (aP2) gene promoter. Tg mice suffer a mild lipodystrophy and exhibit deficiency in adipocyte differentiation. To understand mol. mechanism of the defect in adipocytes, we investigated glyceroneogenesis by examg. the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in adipocytes. In aP2-p65 Tg mice, Pepck expression is inhibited at both the mRNA and protein levels in adipose tissue. The mRNA redn. is a consequence of transcriptional inhibition but not alteration in mRNA stability. The Pepck gene promoter is inhibited by NF-κB, which enhances the corepressor activity through activation of histone deacetylase 3 (HDAC3) in the nucleus. HDAC3 suppresses Pepck transcription by inhibiting the transcriptional activators, peroxisome proliferator-activated receptor-γ, and cAMP response element binding protein. The NF-κB activity is abolished by Hdac3 knockdown or inhibition of HDAC3 catalytic activity. In a chromatin immunopptn. assay, HDAC3 interacts with peroxisome proliferator-activated receptor-γ and cAMP response element binding protein in the Pepck promoter when NF-κB is activated by TNF-α. These results suggest that HDAC3 mediates NF-κB activity to repress Pepck transcription. This mechanism is responsible for inhibition of glyceroneogenesis in adipocytes, which contributes to lipodystrophy in the aP2-p65 Tg mice.
- 216Schmitt, H. M.; Pelzel, H. R.; Schlamp, C. L.; Nickells, R. W. Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injury. Mol. Neurodegener. 2014, 9, 39, DOI: 10.1186/1750-1326-9-39[Crossref], [PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVOmsA%253D%253D&md5=7fcd2b357933611c9c56473cca0b4c74Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injurySchmitt, Heather M.; Pelzel, Heather R.; Schlamp, Cassandra L.; Nickells, Robert W.Molecular Neurodegeneration (2014), 9 (), 39/1-39/15, 15 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: Optic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program. Nuclear atrophy, including global histone deacetylation, heterochromatin formation, shrinkage and collapse of nuclear structure, and the silencing of normal gene expression, comprise an important obstacle to overcome in therapeutic approaches to preserve neuronal function. Several studies have implicated histone deacetylases (HDACs) in the early stages of neuronal cell death, including RGCs. Importantly, these neurons exhibit nuclear translocation of HDAC3 shortly after optic nerve damage. Addnl., HDAC3 activity has been reported to be selectively toxic to neurons. Results: RGC-specific conditional knockout of Hdac3 was achieved by transducing the RGCs of Hdac3fl/fl mice with an adeno-assocd. virus serotype 2 carrying CRE recombinase and GFP (AAV2-Cre/GFP). Controls included similar viral transduction of Rosa26fl/fl reporter mice. Optic nerve crush (ONC) was then performed on eyes. The ablation of Hdac3 in RGCs resulted in significant amelioration of characteristics of ONC-induced nuclear atrophy such as H4 deacetylation, heterochromatin formation, and the loss of nuclear structure. RGC death was also significantly reduced. Interestingly, loss of Hdac3 expression did not lead to protection against RGC-specific gene silencing after ONC, although this effect was achieved using the broad spectrum inhibitor, Trichostatin A. Conclusion: Although other HDACs may be responsible for gene expression changes in RGCs, our results indicate a crit. role for HDAC3 in nuclear atrophy in RGC apoptosis following axonal injury. This study provides a framework for studying the roles of other prevalent retinal HDACs in neuronal death as a result of axonal injury.
- 217Schmitt, H. M.; Schlamp, C. L.; Nickells, R. W. Targeting HDAC3 activity with RGFP966 protects against retinal ganglion cell nuclear atrophy and apoptosis after optic nerve injury. J. Ocul. Pharmacol. Ther. 2018, 34, 260– 273, DOI: 10.1089/jop.2017.0059[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntFWgs7w%253D&md5=a8b21a3a3afdc29f11b68d283cdfbc0bTargeting HDAC3 Activity with RGFP966 Protects Against Retinal Ganglion Cell Nuclear Atrophy and Apoptosis After Optic Nerve InjurySchmitt, Heather M.; Schlamp, Cassandra L.; Nickells, Robert W.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (3), 260-273CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: HDAC3 regulates nuclear atrophy as an early response to axonal injury in retinal ganglion cells (RGCs) following optic nerve crush (ONC). Since conditional knockout of Hdac3 prevents nuclear atrophy post ONC, HDAC3 selective inhibition with RGFP966 through localized and systemic dosing of RGFP966 is necessary for application to acute and chronic models of optic nerve injury. Methods: C57BL/6 mice were injected intravitreally with 1-10μM RGFP966 immediately following ONC, and retinas were analyzed at 5, 7, and 14 days for metrics of nuclear atrophy and cell loss. Mice were similarly assessed after i.p. (IP) injections with RGFP966 doses of 2-10 mg/kg, and eyes were harvested at 5, 14, and 28 days after ONC. H&E and BrdU staining were used to analyze toxicity to off-target tissues after 14 days of daily treatment with RGFP966. Results: A single intravitreal injection of RGFP966 prevented histone deacetylation, heterochromatin formation, apoptosis, and DNA damage at 5 and 7 days post ONC. After IP injection, RGFP966 bioavailability in the retina reached peak concn. within 1 h after injection and then rapidly declined. A single IP injection of 2-10 mg/kg RGFP966, significantly prevented histone deacetylation. Repeated IP injections of 2 mg/kg RGFP966 over the course of 2 and 4 wk post ONC prevented RGC loss. There were no significant toxic or antiproliferative effects to off-target tissues in mice treated daily for 14 days with RGFP966. Conclusion: Inhibition of HDAC3 activity with systemic dosing of RGFP966 prevents apoptosis-related histone deacetylation and attenuates RGC loss after acute optic nerve injury.
- 218Norwood, J.; Franklin, J. M.; Sharma, D.; D’Mello, S. R. Histone deacetylase 3 is necessary for proper brain development. J. Biol. Chem. 2014, 289, 34569– 34582, DOI: 10.1074/jbc.M114.576397[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVSnsA%253D%253D&md5=cb6d33ef429d400628e22220d2b8cf99Histone deacetylase 3 is necessary for proper brain developmentNorwood, Jordan; Franklin, Jade M.; Sharma, Dharmendra; D'Mello, Santosh R.Journal of Biological Chemistry (2014), 289 (50), 34569-34582, 15 pp.CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The functional role of histone deacetylase 3 (HDAC3) in the developing brain has yet to be elucidated. We show that mice lacking HDAC3 in neurons and glia of the central nervous system, Nes-Cre/HDAC3 conditional KO mice, show major abnormalities in the cytoarchitecture of the neocortex and cerebellum and die within 24 h of birth. Later-born neurons do not localize properly in the cortex. A similar mislocalization is obsd. with cerebellar Purkinje neurons. Although the proportion of astrocytes is higher than normal, the nos. of oligodendrocytes are reduced. In contrast, conditional knockout of HDAC3 in neurons of the forebrain and certain other brain regions, using Thy1-Cre and calcium/calmodulin dependent protein kinase II α-Cre for ablation, produces no overt abnormalities in the organization of cells within the cortex or of cerebellar Purkinje neurons at birth. However, both lines of conditional knockout mice suffer from progressive hind limb paralysis and ataxia and die around 6 wk after birth. The mice display an increase in overall nos. of cells, higher nos. of astrocytes, and Purkinje neuron degeneration. Taken together, our results demonstrate that HDAC3 plays an essential role in regulating brain development, with effects on both neurons and glia in different brain regions.
- 219Herman, D.; Jenssen, K.; Burnett, R.; Soragni, E.; Perlman, S. L.; Gottesfeld, J. M. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat. Chem. Biol. 2006, 2, 551– 558, DOI: 10.1038/nchembio815[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xps1aht7k%253D&md5=a4a3af8104d80260807087dcb5c3c178Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxiaHerman, David; Jenssen, Kai; Burnett, Ryan; Soragni, Elisabetta; Perlman, Susan L.; Gottesfeld, Joel M.Nature Chemical Biology (2006), 2 (10), 551-558, S551/1-S551/13CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Expansion of GAA·TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the mol. basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these mols. directly affect the histones assocd. with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.
- 220Xu, C.; Soragni, E.; Chou, C. J.; Herman, D.; Plasterer, H. L.; Rusche, J. R.; Gottesfeld, J. M. Chemical probes identify a role for histone deacetylase 3 in Friedreich’s Ataxia gene silencing. Chem. Biol. 2009, 16, 980– 989, DOI: 10.1016/j.chembiol.2009.07.010[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFynsLrJ&md5=6157d7f06142b195ef686a540b459a28Chemical Probes Identify a Role for Histone Deacetylase 3 in Friedreich's Ataxia Gene SilencingXu, Chunping; Soragni, Elisabetta; Chou, C. James; Herman, David; Plasterer, Heather L.; Rusche, James R.; Gottesfeld, Joel M.Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 980-989CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chem. approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chem. addn. of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear ext. prepd. from human lymphoblasts with the trifunctional probe, followed by biotin addn. through click chem., streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Addnl. inhibitors with different HDAC specificity profiles were synthesized, and results from transcription expts. in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia.
- 221Xia, M. X.; Zhao, Q. C.; Zhang, H.; Chen, Y. T.; Yuan, Z. Q.; Xu, Y.; Zhang, M. J. Proteomic analysis of HDAC3 selective inhibitor in the regulation of inflammatory response of primary microglia. Neural Plast. 2017, 2017, 6237351, DOI: 10.1155/2017/6237351[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czmtF2ksA%253D%253D&md5=643cb3e29100fa3f60d9c121a8c25530Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary MicrogliaXia Mingxu; Zhao Qiuchen; Zhang He; Chen Yanting; Xu Yun; Zhang Meijuan; Yuan ZengqiangNeural plasticity (2017), 2017 (), 6237351 ISSN:.HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.
- 222Jia, H.; Wang, Y.; Morris, C. D.; Jacques, V.; Gottesfeld, J. M.; Rusche, J. R.; Thomas, E. A. The effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington’s disease mice. PLoS One 2016, 11, e0152498 DOI: 10.1371/journal.pone.0152498[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFaltbbF&md5=9e31b637a747319539e674c6c5c8adccThe effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington's disease miceJia, Haiqun; Wang, Ying; Morris, Charles D.; Jacques, Vincent; Gottesfeld, Joel M.; Rusche, James R.; Thomas, Elizabeth A.PLoS One (2016), 11 (3), e0152498/1-e0152498/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)An important epigenetic modification in Huntington's disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal vol. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quant. PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif), a hormone immune modulator assocd. with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its assocd. downstream effects.
- 223Suelves, N.; Kirkham-McCarthy, L.; Lahue, R. S.; Ginés, S. A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington’s disease mice. Sci. Rep. 2017, 7, 6082, DOI: 10.1038/s41598-017-05125-2[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjpslCmsQ%253D%253D&md5=0c384551190fd157825f8a29f675a79fA selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease miceSuelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Kirkham-McCarthy Lucy; Lahue Robert S; Lahue Robert SScientific reports (2017), 7 (1), 6082 ISSN:.Huntington's disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating Hdh(Q111) knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.
- 224Rumbaugh, G.; Sillivan, S. E.; Ozkan, E. D.; Rojas, C. S.; Hubbs, C. R.; Aceti, M.; Kilgore, M.; Kudugunti, S.; Puthanveettil, S. V.; Sweatt, J. D.; Rusche, J.; Miller, C. A. Pharmacological selectivity within class i histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology 2015, 40, 2307– 2316, DOI: 10.1038/npp.2015.93[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFOqurk%253D&md5=8b92747830ff7b8b31ce46fb00aa6e5aPharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory RescueRumbaugh, Gavin; Sillivan, Stephanie E.; Ozkan, Emin D.; Rojas, Camilo S.; Hubbs, Christopher R.; Aceti, Massimiliano; Kilgore, Mark; Kudugunti, Shashi; Puthanveettil, Sathyanarayanan V.; Sweatt, J. David; Rusche, James; Miller, Courtney A.Neuropsychopharmacology (2015), 40 (10), 2307-2316CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)Histone deacetylases (HDACs) are promising therapeutic targets for neurol. and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the mol., cellular and behavioral level are limited. Therefore, we interrogated the biol. effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compds. for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine d., while HDAC3 inhibition was ineffective. Genome-wide gene expression anal. by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathol. brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.
- 225Rogge, G. A.; Singh, H.; Dang, R.; Wood, M. A. HDAC3 is a negative regulator of cocaine-context-associated memory formation. J. Neurosci. 2013, 33, 6623– 6632, DOI: 10.1523/JNEUROSCI.4472-12.2013[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtl2jtrfE&md5=69819c3e67ab3fe110c11fc7bbecde9fHDAC3 is a negative regulator of cocaine-context-associated memory formationRogge, George A.; Singh, Harsimran; Dang, Richard; Wood, Marcelo A.Journal of Neuroscience (2013), 33 (15), 6623-6632CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Cocaine-induced neuroplasticity mediated by histone acetylating and deacetylating enzymes may contribute to addiction-like behaviors. For example, overexpression of histone deacetylases (HDACs) 4 or 5 in the nucleus accumbens suppresses cocaine-induced conditioned place preference (CPP) acquisition in mice. HDAC4 and HDAC5 are known to interact with HDAC3, but the role of HDAC3 in cocaine-induced behaviors has never been examd. In this study, we address the hypothesis that HDAC3 is a neg. regulator of cocaine-context-assocd. memory formation in mice. We examd. the role of HDAC3 during the conditioning phase of CPP, when the mouse has the opportunity to form an associative memory between the cocaine-paired context and the subjective effects of cocaine. To address this hypothesis, Hdac3flox/flox and Hdac3+/+ mice (generated from a C57BL/6 background) were infused into the nucleus accumbens with adeno-assocd. virus expressing Cre recombinase to create focal, homozygous Hdac3 deletions. Hdac3flox/flox mice exhibit significantly enhanced CPP acquisition, which is correlated with increased gene expression during the consolidation phase of acquisition. Increased gene expression of c-Fos and Nr4a2 is correlated with decreased HDAC3 occupancy and increased histone H4 lysine 8 acetylation at their promoters. The results from this study demonstrate that HDAC3 neg. regulates cocaine-induced CPP acquisition.
- 226Malvaez, M.; McQuown, S. C.; Rogge, G. A.; Astarabadi, M.; Jacques, V.; Carreiro, S.; Rusche, J. R.; Wood, M. A. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 2647– 2652, DOI: 10.1073/pnas.1213364110[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsVCnsb4%253D&md5=37fd432cbf96bd2c30b7d5ac9eefcf45HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent mannerMalvaez, Melissa; McQuown, Susan C.; Rogge, George A.; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R.; Wood, Marcelo A.Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (7), 2647-2652, S2647/1-S2647/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to neg. effects on performance or reconsolidation. These are key distinctions with regard to any compd. being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.
- 227McQuown, S. C.; Barrett, R. M.; Matheos, D. P.; Post, R. J.; Rogge, G. A.; Alenghat, T.; Mullican, S. E.; Jones, S.; Rusche, J. R.; Lazar, M. A.; Wood, M. A. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 2011, 31, 764– 774, DOI: 10.1523/JNEUROSCI.5052-10.2011[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ars70%253D&md5=02f22e34e095ac5fe5e5b6217821b8ccHDAC3 is a critical negative regulator of long-term memory formationMcQuown, Susan C.; Barrett, Ruth M.; Matheos, Dina P.; Post, Rebecca J.; Rogge, George A.; Alenghat, Theresa; Mullican, Shannon E.; Jones, Steven; Rusche, James R.; Lazar, Mitchell A.; Wood, Marcelo A.Journal of Neuroscience (2011), 31 (2), 764-774CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation neg. regulates transcription. The interplay between histone acetyltranserases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examd. the role of HDAC3 in long-term memory using a combined genetic and pharmacol. approach. We used HDAC3-FLOX genetically modified mice in combination with adeno-assocd. virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochem. showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examd. expression of genes implicated in long-term memory from dorsal hippocampal punches using quant. reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3-FLOX mice compared with wild-type controls. Memory enhancements obsd. in HDAC3-FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 neg. regulates memory formation. Together, these findings demonstrate a crit. role for HDAC3 in the mol. mechanisms underlying long-term memory formation.
- 228Sanchez, S.; Lemmens, S.; Baeten, P.; Sommer, D.; Dooley, D.; Hendrix, S.; Fabregas, M. G. HDAC3 inhibition promotes alternative activation of macrophages but does not affect functional recovery after spinal cord injury. Exp. Neurobiol. 2018, 27, 437– 452, DOI: 10.5607/en.2018.27.5.437[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crgtFeisQ%253D%253D&md5=e8fe8c84a3f84a0bfc4c16ea7cfb5909HDAC3 Inhibition Promotes Alternative Activation of Macrophages but Does Not Affect Functional Recovery after Spinal Cord InjurySanchez Selien; Lemmens Stefanie; Baeten Paulien; Sommer Daniela; Hendrix Sven; Gou Fabregas Myriam; Dooley DearbhaileExperimental neurobiology (2018), 27 (5), 437-452 ISSN:1226-2560.After spinal cord injury (SCI), monocyte derived macrophages play a detrimental role. Histone deacetylases (HDACs) are central epigenetic regulators of macrophage-polarization. We hypothesized that HDAC3 inhibition suppresses the pro-inflammatory macrophage phenotype (M1), promotes the anti-inflammatory phenotype (M2) and improves functional recovery after SCI. Therefore, two inhibitors of HDAC3 were selected, namely scriptaid and RGFP966. The impact on macrophage polarization was studied by investigating the effect on gene and protein expression of selected M1 and M2 markers. We show that scriptaid differentially influences M1 and M2 markers. It increases CD86 and iNOS gene expression and decreases GPR18, CD38, FPR2 and Arg-1 gene expression as well as the production of IL-6 and NO. RGFP966 primarily increased the expression of the M2 markers Arg-1 and Ym1 and reduced the production of IL-6 (M1). RGFP966 and scriptaid reduced the formation of foamy macrophages. Finally, to investigate the impact of HDAC3 inhibition on functional recovery after SCI, we studied the effects of RGFP966 and scriptaid in an in vivo T-cut hemisection SCI model. Histological analyses were performed on spinal cord sections to determine lesion size and astrogliosis, demyelinated area and selected infiltrating immune cells. RGFP966 and scriptaid did not affect functional recovery or histopathological outcome after SCI. In conclusion, these results indicate that specific HDAC3 inhibition with RGFP966 promotes alternative activation of macrophages and reduces the formation of foamy macrophages, but does not lead to a better functional recovery after SCI.
- 229Yang, X.; Wu, Q.; Zhang, L.; Feng, L. Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in rats. Front. Mol. Neurosci. 2016, 9, 131, DOI: 10.3389/fnmol.2016.00131[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtV2itrbF&md5=91895280c5b732f55f01cf5d7e283956Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in ratsYang, Xiaoyu; Wu, Qimei; Zhang, Lei; Feng, LinyinFrontiers in Molecular Neuroscience (2016), 9 (), 131/1-131/14CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)Brain ischemic preconditioning (PC) provides vital insights into the endogenous protection against stroke. Genomic and epigenetic responses to PC condition the brain into a state of ischemic tolerance. Notably, PC induces the elevation of histone acetylation, consistent with evidence that histone deacetylase (HDAC) inhibitors protect the brain from ischemic injury. However, less is known about the specific roles of HDACs in this process. HDAC3 has been implicated in several neurodegenerative conditions. Deletion of HDAC3 confers protection against neurotoxicity and neuronal injury. Here, we hypothesized that inhibition of HDAC3 may contribute to the neuronal survival elicited by PC. To address this notion, PC and transient middle cerebral artery occlusion (MCAO) were conducted in Sprague-Dawley rats. Addnl., primary cultured cortical neurons were used to identify the modulators and effectors of HDAC3 involved in PC. We found that nuclear localization of HDAC3 was significantly reduced following PC in vivo and in vitro. Treatment with the HDAC3-specific inhibitor, RGFP966, mimicked the neuroprotective effects of PC 24 h and 7 days after MCAO, causing a reduced infarct vol. and less Fluoro-Jade C staining. Improved functional outcomes were obsd. in the neurol. score and rotarod test. We further showed that attenuated recruitment of HDAC3 to promoter regions following PC potentiates transcriptional initiation of genes including Hspa1a, Bcl2l1, and Prdx2, which may underlie the mechanism of protection. In addn., PC-activated calpains were implicated in the cleavage of HDAC3. Pretreatment with calpeptin blockaded the attenuated nuclear distribution of HDAC3 and the protective effect of PC in vivo. Collectively, these results demonstrate that the inhibition of HDAC3 preconditions the brain against ischemic insults, indicating a new approach to evoke endogenous protection against stroke.
- 230Duncan, C. E.; An, M. C.; Papanikolaou, T.; Rugani, C.; Vitelli, C.; Ellerby, L. M. Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model. Mol. Neurodegener. 2013, 8, 42, DOI: 10.1186/1750-1326-8-42[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsVyhs7c%253D&md5=6bc7fc14246895d5b04488775df303e7Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse modelDuncan, Carlotta E.; An, Mahru C.; Papanikolaou, Theodora; Rugani, Caitlin; Vitelli, Cathy; Ellerby, Lisa M.Molecular Neurodegeneration (2013), 8 (), 42/1-42/14, 14 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity assocd. with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 phys. interacts with ataxin-7. The phys. interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors.
- 231Krishna, K.; Behnisch, T.; Sajikumar, S. Inhibition of histone deacetylase 3 restores amyloid-β oligomer-induced plasticity deficit in hippocampal CA1 pyramidal neurons. J. Alzheimer's Dis. 2016, 51, 783– 791, DOI: 10.3233/JAD-150838[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlt1SksLY%253D&md5=55aa2393e083fd5654a60fd878527a58Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal NeuronsKrishna, Kumar; Behnisch, Thomas; Sajikumar, Sreedharan; Arancio, OttavioJournal of Alzheimer's Disease (2016), 51 (3), 783-791CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Neurodegenerative diseases such as Alzheimer's disease (AD) are assocd. with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known crit. epigenetic neg. regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.
- 232Gillespie, J.; Savic, S.; Wong, C.; Hempshall, A.; Inman, M.; Emery, P.; Grigg, R.; McDermott, M. F. Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum. 2012, 64, 418– 422, DOI: 10.1002/art.33382[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yru7c%253D&md5=6ac55ccb9ffcd2c1d4e2d93dabcdc71eHistone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patientsGillespie, Justin; Savic, Sinisa; Wong, Chi; Hempshall, Aiden; Inman, Martyn; Emery, Paul; Grigg, Ronald; McDermott, Michael F.Arthritis & Rheumatism (2012), 64 (2), 418-422CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine prodn. Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 wk of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine prodn. in both RA and healthy PBMCs were assessed by ELISA. RA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 wk of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) prodn. in both RA and healthy PBMCs and of interferon-γ (IFNγ) prodn. in healthy PBMCs; IFNγ was not produced by RA PBMCs. MI192 inhibited TNF prodn. at high concns. and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 μM-5 nM. HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, resp.) were found to regulate cytokine prodn. from PBMCs, but their effects were cell type and compd. specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clin. characterization and evaluation for adverse effects is needed.
- 233Chen, X.; Barozzi, I.; Termanini, A.; Prosperini, E.; Recchiuti, A.; Dalli, J.; Mietton, F.; Matteoli, G.; Hiebert, S.; Natoli, G. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, E2865– E2874, DOI: 10.1073/pnas.1121131109[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Wmsb%252FO&md5=15742ff99ed4eee55d890d640daee450Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophagesChen, Xuefen; Barozzi, Iros; Termanini, Alberto; Prosperini, Elena; Recchiuti, Antonio; Dalli, Jesmond; Mietton, Flore; Matteoli, Gianluca; Hiebert, Scott; Natoli, GioacchinoProceedings of the National Academy of Sciences of the United States of America (2012), 109 (42), E2865-E2874, SE2865/1-SE2865/89CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and assocd. gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chem. inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.
- 234Zhang, H.; Ji, L.; Yang, Y.; Wei, Y.; Zhang, X.; Gang, Y.; Lu, J.; Bai, L. The Therapeutic effects of treadmill exercise on osteoarthritis in rats by inhibiting the HDAC3/NF-KappaB pathway in vivo and in vitro. Front. Physiol. 2019, 10, 1060, DOI: 10.3389/fphys.2019.01060[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MrkvVKksQ%253D%253D&md5=d761f4b0ceb59380384ae4595381fa3eThe Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitroZhang He; Yang Yue; Wei Yingliang; Lu Jinghan; Bai Lunhao; Ji Lu; Zhang Xiaoning; Gang YiFrontiers in physiology (2019), 10 (), 1060 ISSN:1664-042X.Osteoarthritis (OA) is a disease characterized by non-bacterial inflammation. Histone deacetylase 3 (HDAC3) is a crucial positive regulator in the inflammation that leads to the development of non-OA inflammatory disease. However, the precise involvement of HDAC3 in OA is still unknown, and the underlying mechanism of exercise therapy in OA requires more research. We investigated the involvement of HDAC3 in exercise therapy-treated OA. Expression levels of HDAC3, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), HDAC3 and nuclear factor-kappaB (NF-kappaB) were measured by western blotting, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Cartilage damage and OA evaluation were measured by hematoxylin and eosin staining and Toluidine blue O staining according to the Mankin score and OARSI score, respectively. We found that moderate-intensity treadmill exercise could relieve OA. Meanwhile, the expression of HDAC3, MMP-13, ADAMTS-5 and NF-kappaB decreased, and collagen II increased in the OA + moderate-intensity treadmill exercise group (OAM) compared with the OA group (OAG) or OA + high- or low-intensity treadmill exercise groups (OAH or OAL). Furthermore, we found the selective HDAC3 inhibitor RGFP966 could also alleviate inflammation in OA rat model through inhibition of nuclear translocation of NF-kappaB. To further explore the relationship between HDAC3 and NF-kappaB, we investigated the change of NF-kappaB relocation in IL-1β-treated chondrocytes under the stimulation of RGFP966. We found that RGFP966 could inhibit the expression of inflammatory markers of OA via regulation of HDAC3/NF-kappaB pathway. These investigations revealed that RGFP966 is therefore a promising new drug for treating OA.
- 235Hoeksema, M. A.; Gijbels, M. J.; Van den Bossche, J.; Velden, S.; Sijm, A.; Neele, A. E.; Seijkens, T.; Stöger, J. L.; Meiler, S.; Boshuizen, M. C.; Dallinga-Thie, G. M.; Levels, J. H.; Boon, L.; Mullican, S. E.; Spann, N. J.; Cleutjens, J. P.; Glass, C. K.; Lazar, M. A.; Vries, C. J.; Biessen, E. A.; Daemen, M. J.; Lutgens, E.; Winther, M. P. Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol. Med. 2014, 6, 1124– 1132, DOI: 10.15252/emmm.201404170[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVCmur%252FF&md5=6ada26dd828f8bde3c756c0ba6632e32Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesionsHoeksema, Marten A.; Gijbels, Marion JJ; Van den Bossche, Jan; van der Velden, Saskia; Sijm, Ayestha; Neele, Annette E.; Seijkens, Tom; Stoeger, J. Lauran; Meiler, Svenja; Boshuizen, Marieke CS; Dallinga-Thie, Geesje M.; Levels, Johannes HM; Boon, Louis; Mullican, Shannon E.; Spann, Nathanael J.; Cleutjens, Jack P.; Glass, Chris K.; Lazar, Mitchell A.; de Vries, Carlie JM; Biessen, Erik AL; Daemen, Mat JAP; Lutgens, Esther; de Winther, Menno PJEMBO Molecular Medicine (2014), 6 (9), 1124-1132CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen prodn. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 assocd. with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease.
- 236Lewandowski, S. L.; Janardhan, H. P.; Trivedi, C. M. Histone Deacetylase 3 coordinates deacetylase-independent epigenetic silencing of transforming growth factor-β1 (TGF-β1) to orchestrate second heart field development. J. Biol. Chem. 2015, 290, 27067– 27089, DOI: 10.1074/jbc.M115.684753[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyrtrbP&md5=77e241bf9787f93b2cae75c62957b6c7Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field DevelopmentLewandowski, Sara L.; Janardhan, Harish P.; Trivedi, Chinmay M.Journal of Biological Chemistry (2015), 290 (45), 27067-27089CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is assocd. with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacol. inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.
- 237Cavasin, M. A.; Demos-Davies, K.; Horn, T. R.; Walker, L. A.; Lemon, D. D.; Birdsey, N.; Weiser-Evans, M. C.; Harral, J.; Irwin, D. C.; Anwar, A.; Yeager, M. E.; Li, M.; Watson, P. A.; Nemenoff, R. A.; Buttrick, P. M.; Stenmark, K. R.; McKinsey, T. A. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ. Res. 2012, 110, 739– 748, DOI: 10.1161/CIRCRESAHA.111.258426[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtV2nu7g%253D&md5=f419a07195352059951c5bf76cbb30fdSelective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative MechanismCavasin, Maria A.; Demos-Davies, Kim; Horn, Todd R.; Walker, Lori A.; Lemon, Douglas D.; Birdsey, Nicholas; Weiser-Evans, Mary C. M.; Harral, Julie; Irwin, David C.; Anwar, Adil; Yeager, Michael E.; Li, Min; Watson, Peter A.; Nemenoff, Raphael A.; Buttrick, Peter M.; Stenmark, Kurt R.; McKinsey, Timothy A.Circulation Research (2012), 110 (5), 739-748CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with assocd. right ventricular cardiac remodeling are poorly understood. Objective: This study was performed to assess the utility of selective small-mol. inhibitors of class I HDACs in a preclin. model of pulmonary hypertension. Methods and results: Rats were exposed to hypobaric hypoxia for 3 wk in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compd. reduced pulmonary arterial pressure more dramatically than tadalafil, a std.-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a pos. impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was assocd. with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathol. gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. Conclusions: By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator stds. of care.
- 238Kee, H. J.; Kim, G. R.; Lin, M. Q.; Choi, S. Y.; Ryu, Y.; Jin, L.; Piao, Z. H.; Jeong, M. H. Expression of class I and class II a/b histone deacetylase is dysregulated in hypertensive animal models. Korean Circ. J. 2017, 47, 392– 400, DOI: 10.4070/kcj.2016.0266[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1eqsL%252FJ&md5=b5841463ecc31ecca07bd32804091e12Expression of class I and class II a/b histone deacetylase is dysregulated in hypertensive animal modelsKee, Hae Jin; Kim, Gwi Ran; Lin, Ming Ouan; Choi, Sin Young; Ryu, Yuhee; Jin, Li; Piao, Zhe Hao; Jeong, Myung HoKorean Circulation Journal (2017), 47 (3), 392-400CODEN: KCJOA9; ISSN:1738-5520. (Korean Society of Cardiology)Background and Objectives: Dysregulation of histone deacetylase expression and enzymic activity is assocd. with a no. of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models. Materials and Methods: We used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to irduce hypertension, via osmotic mini-pump for 2 wk, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine Me ester (L-NAME) to induce hypertension. Results: SHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were obsd. in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addn., a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR. Conclusion: These results indicate that dysregulation of class I and class II HDAC protein is closely assocd. with chronic hypertension.
- 239Sharifi-Sanjani, M.; Shoushtari, A. H.; Quiroz, M.; Baust, J.; Sestito, S. F.; Mosher, M.; Ross, M.; McTiernan, C. F.; St. Croix, C. M.; Bilonick, R. A.; Champion, H. C.; Isenberg, J. S. Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3. J. Am. Heart Assoc. 2014, 3, e000670 DOI: 10.1161/JAHA.113.000670[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgu73K&md5=27b9795123d46ac46c07be40348f01b0Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3Sharifi-Sanjani, Maryam; Shoushtari, Ali Hakim; Quiroz, Marisol; Baust, Jeffrey; Sestito, Samuel F.; Mosher, Mackenzie; Ross, Mark; McTiernan, Charles F.; St. Croix, Claudette M.; Bilonick, Richard A.; Champion, Hunter C.; Isenberg, Jeffrey S.Journal of the American Heart Association (2014), 3 (3), e000670/1-e000670/22, 22 pp.CODEN: JAHABZ; ISSN:2047-9980. (Wiley-Blackwell)Background: Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger nos. of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high-affinity secreted ligand, thrombospondin 1 (TSP 1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed. Methods and Results: In exptl. LVHF TSP 1-CD47 signaling is increased concurrent with up-regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)-driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1-derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca2+/calmodulin protein kinase II (CaMKII)-dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacol. inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals. Conclusions: These data identify a proximate role for the TSP 1-CD47 axis in promoting LVHF by CaKMII-mediated up-regulation of HDAC3 and suggest novel therapeutic opportunities.
- 240Lyu, X.; Hu, M.; Peng, J.; Zhang, X.; Sanders, Y. Y. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Ther. Adv. Chronic Dis. 2019, 10, 2040622319862697, DOI: 10.1177/2040622319862697
- 241Ryu, Y.; Kee, H. J.; Sun, S.; Seok, Y. M.; Choi, S. Y.; Kim, G. R.; Kee, S. J.; Pflieger, M.; Kurz, T.; Kim, H. S.; Jeong, M. H. Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertension. PLoS One 2019, 14, e0213186 DOI: 10.1371/journal.pone.0213186[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1SmtLo%253D&md5=baf89fbc5960f31d05eb854fab2db203Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertensionRyu, Yuhee; Kee, Hae Jin; Sun, Simei; Seok, Young Mi; Choi, Sin Young; Kim, Gwi Ran; Kee, Seung-Jung; Pflieger, Marc; Kurz, Thomas; Kim, Hyung-Seok; Jeong, Myung HoPLoS One (2019), 14 (3), e0213186CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg-1·day-1) was not enough to induce NO prodn. in vivo. In addn., MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-a, IL-1β, and MCP-1, as well as adhesion mols. Histol. anal. showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration. Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.
- 242Zhao, B.; Yuan, Q.; Hou, J. B.; Xia, Z. Y.; Zhan, L. Y.; Li, M.; Jiang, M.; Gao, W. W.; Liu, L. Inhibition of HDAC3 ameliorates cerebral ischemia reperfusion injury in diabetic mice in vivo and in vitro. J. Diabetes Res. 2019, 2019, 8520856, DOI: 10.1155/2019/8520856[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbns1KjsA%253D%253D&md5=c182705768ad3a5bedeb4cce0238cbc8Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In VitroZhao Bo; Yuan Quan; Hou Jia-Bao; Xia Zhong-Yuan; Zhan Li-Ying; Li Mei; Jiang Meng; Liu Lian; Gao Wen-WeiJournal of diabetes research (2019), 2019 (), 8520856 ISSN:.Background: A substantial increase in histone deacetylase 3 (HDAC3) expression is implicated in the pathological process of diabetes and stroke. However, it is unclear whether HDAC3 plays an important role in diabetes complicated with stroke. We aimed to explore the role and the potential mechanisms of HDAC3 in cerebral ischemia/reperfusion (I/R) injury in diabetic state. Methods: Diabetic mice were subjected to 1 h ischemia, followed by 24 h reperfusion. PC12 cells were exposed to high glucose for 24 h, followed by 3 h of hypoxia and 6 h of reoxygenation (H/R). Diabetic mice received RGFP966 (the specific HDAC3 inhibitor) or vehicle 30 minutes before the middle cerebral artery occlusion (MCAO), and high glucose-incubated PC12 cells were pretreated with RGFP966 or vehicle 6 h before H/R. Results: HDAC3 inhibition reduced the cerebral infarct volume, ameliorated pathological changes, improved the cell viability and cytotoxicity, alleviated apoptosis, attenuated oxidative stress, and enhanced autophagy in cerebral I/R injury model in diabetic state in vivo and in vitro. Furthermore, we found that the expression of HDAC3 was remarkably amplified, and the Bmal1 expression was notably decreased in diabetic mice with cerebral I/R, whereas this phenomenon was obviously reversed by RGFP966 pretreatment. Conclusions: These results suggested that the HDAC3 was involved in the pathological process of the complex disease of diabetic stroke. Suppression of HDAC3 exerted protective effects against cerebral I/R injury in diabetic state in vivo and in vitro via the modulation of oxidative stress, apoptosis, and autophagy, which might be mediated by the upregulation of Bmal1.
- 243Zhang, J.; Xu, Z.; Gu, J. L.; Jiang, S. Z.; Liu, Q.; Zheng, Y.; Freedman, J. H.; Sun, J.; Cai, L. HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetesinduced liver damage and FGF21 synthesis and secretion leading to aortic protection. Am. J. Physiol-Endoc M 2018, 315, E150– E162, DOI: 10.1152/ajpendo.00465.2017
- 244Villagra, A.; Ulloa, N.; Zhang, X.; Yuan, Z.; Sotomayor, E.; Seto, E. Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression. J. Biol. Chem. 2007, 282, 35457– 35470, DOI: 10.1074/jbc.M701719200[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlKrsLfE&md5=669b2e6162605b83c5a53be2a2525356Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene ExpressionVillagra, Alejandro; Ulloa, Natalia; Zhang, Xiaohong; Yuan, Zhigang; Sotomayor, Eduardo; Seto, EdwardJournal of Biological Chemistry (2007), 282 (49), 35457-35470CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), E.C. 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochem. functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that histone deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concns. compared with parental cells. Extensive promoter analyses coupled with chromatin immunopptn. assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.
- 245Joshi, A. D.; Barabutis, N.; Birmpas, C.; Dimitropoulou, C.; Thangjam, G.; Cherian-Shaw, M.; Dennison, J.; Catravas, J. D. Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 309, L1410– L1419, DOI: 10.1152/ajplung.00180.2015
- 246Zhang, X.; Ozawa, Y.; Lee, H.; Wen, Y. D.; Tan, T. H.; Wadzinski, B. E.; Seto, E. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 2005, 19, 827– 839, DOI: 10.1101/gad.1286005[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1Ojtb4%253D&md5=214fae9f8751105f1df62e448f22e63dHistone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4Zhang, Xiaohong; Ozawa, Yukiyasu; Lee, Heehyoung; Wen, Yu-Der; Tan, Tse-Hua; Wadzinski, Brian E.; Seto, EdwardGenes & Development (2005), 19 (7), 827-839CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Histone deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of histones and nonhistone proteins. Early studies have suggested that HDAC3 activity is regulated by assocn. with the corepressors N-CoR and SMRT. Here the authors demonstrate that, in addn. to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1-122) was both necessary and sufficient for HDAC3-PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and anal. of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein-protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
- 247Gu, L. Z.; Sun, H.; Chen, J. H. Histone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathways. Biomed. Pharmacother. 2017, 85, 756– 762, DOI: 10.1016/j.biopha.2016.11.094[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2mtbvF&md5=f10d3c567f3dcc915cea3a956f3b680fHistone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathwaysGu, Li-Zhi; Sun, Hong; Chen, Jian-HuiBiomedicine & Pharmacotherapy (2017), 85 (), 756-762CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Acute lung injury (ALI) as a serious disease with high mortality has been emphasized as a threat to human health and life. Accumulating studies demonstrated that PM2.5 plays a significant role in metabolic and lung diseases. Histone deacetylases 3 (HDAC3) is an important regulator in control of gene transcription, required in up-regulation of inflammation-related signaling, and has been known as a key hotpot in treating a lot of chronic inflammatory diseases. TGF-β/Smad signaling pathway has been proven to be of significance in fibrosis development. Our results found that PM2.5 induced lung function injury in WT mice with a inflammatory responses through the activation of TGF-β/Smad signaling pathways, resulting in lung injury. Of note, HDAC3-deficient mice after PM2.5 administration further promoted TGF-β/Smad signaling pathways activation. In addn., TLR4, p-NF-κB and p-IκBα indicated that HDAC3 knockout mice have a higher inflammation-related signals expression in lung tissue than WT mice after PM2.5 administration, resulting in pro-inflammatory cytokines releasing. Moreover, in vitro expt. of lung epithelial cells challenged with PM2.5, further indicated that TGF-β/Smad2/3 was involved in fibrosis development, leading to inflammation response. Also, the activation of TLR4/NF-κB could be obsd. in PM2.5-induced lung epithelial cells, leading to inflammation infiltration. These results indicate a new therapeutic target to protect against lung injury caused by PM2.5.
- 248Jung, S. B.; Kim, C. S.; Naqvi, A.; Yamamori, T.; Mattagajasingh, I.; Hoffman, T. A.; Cole, M. P.; Kumar, A.; Dericco, J. S.; Jeon, B. H.; Irani, K. Histone deacetylase 3 antagonizes aspirin-stimulated endothelial nitric oxide production by reversing aspirin-induced lysine acetylation of endothelial nitric oxide synthase. Circ. Res. 2010, 107, 877– 887, DOI: 10.1161/CIRCRESAHA.110.222968[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Gku7jJ&md5=f8b1fffcd599f622e09c3e04f6b9004aHistone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide SynthaseJung, Saet-Byel; Kim, Cuk-Seong; Naqvi, Asma; Yamamori, Tohru; Mattagajasingh, Ilwola; Hoffman, Timothy A.; Cole, Marsha P.; Kumar, Ajay; DeRicco, Jeremy S.; Jeon, Byeong-Hwa; Irani, KaikobadCirculation Research (2010), 107 (7), 877-887CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endothelium-dependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacol. target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known. Objective: To det. the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO prodn. by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO prodn. by reversing acetylation of functionally crit. eNOS lysine residues. Methods and results: Low concns. of aspirin induce lysine acetylation of eNOS, stimulating eNOS enzymic activity and endothelial NO prodn. in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin-stimulated binding of eNOS to calmodulin and eNOS-derived NO prodn. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation. Conclusions: Lysine acetylation of eNOS is a posttranslational protein modification supporting low-dose aspirin-induced vasoprotection. HDAC3, by deacetylating aspirin-acetylated eNOS, antagonizes aspirin-stimulated endothelial prodn. of NO.
- 249Ziesché, E.; Kettner-Buhrow, D.; Weber, A.; Wittwer, T.; Jurida, L.; Soelch, J.; Müller, H.; Newel, D.; Kronich, P.; Schneider, H.; Dittrich-Breiholz, O.; Bhaskara, S.; Hiebert, S. W.; Hottiger, M. O.; Li, H.; Burstein, E.; Schmitz, M. L.; Kracht, M. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Nucleic Acids Res. 2013, 41, 90– 109, DOI: 10.1093/nar/gks916[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFektQ%253D%253D&md5=b33a4d12e3010f3f78ac438635f16b9eThe coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κBZiesche, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel; Wittwer, Tobias; Jurida, Liane; Soelch, Johanna; Mueller, Helmut; Newel, Doris; Kronich, Petra; Schneider, Heike; Dittrich-Breiholz, Oliver; Bhaskara, Srividya; Hiebert, Scott W.; Hottiger, Michael O.; Li, Haiying; Burstein, Ezra; Schmitz, M. Lienhard; Kracht, MichaelNucleic Acids Research (2013), 41 (1), 90-109CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes contg. silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a pos. regulator of IL-1-induced gene expression. Various exptl. approaches involving RNAi-mediated knockdown, conditional gene deletion or small mol. inhibitors indicate a pos. role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-κB p65 and its deacetylation at various lysines. NF-κB p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-κB p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently obsd. for HDAC inhibitors in (pre)clin. use.
- 250Morioka, N.; Tomori, M.; Zhang, F. F.; Saeki, M.; Hisaoka-Nakashima, K.; Nakata, Y. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells. Biochem. Biophys. Res. Commun. 2016, 469, 151– 157, DOI: 10.1016/j.bbrc.2015.11.086[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFCltr%252FK&md5=d3c181a908f06bf5cb3bff3b8a5cb767Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cellsMorioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, YoshihiroBiochemical and Biophysical Research Communications (2016), 469 (2), 151-157CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Under physiol. conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic mols. such as cytokines and chemokines, amplifying the initial mol.-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metab.-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory mols. following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/mL) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms.
- 251Leus, N. G.; van der Wouden, P. E.; van den Bosch, T.; Hooghiemstra, W. T. R.; Ourailidou, M. E.; Kistemaker, L. E.; Bischoff, R.; Gosens, R.; Haisma, H. J.; Dekker, F. J. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity. Biochem. Pharmacol. 2016, 108, 58– 74, DOI: 10.1016/j.bcp.2016.03.010[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksVWmsrs%253D&md5=6068577165c78778170d77e4065042ecHDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activityLeus, Niek G. J.; van der Wouden, Petra E.; van den Bosch, Thea; Hooghiemstra, Wouter T. R.; Ourailidou, Maria E.; Kistemaker, Loes E. M.; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J.; Dekker, Frank J.Biochemical Pharmacology (Amsterdam, Netherlands) (2016), 108 (), 58-74CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)The increasing no. of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathol. of COPD. Here, we applied the pharmacol. HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was obsd. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymic activity of HDAC 3. Taken together, our findings indicate that pharmacol. HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases.
- 252Lin, W.; Zhang, Q.; Liu, L.; Yin, S.; Liu, Z.; Cao, W. Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease. Kidney Int. 2017, 92, 669– 679, DOI: 10.1016/j.kint.2017.02.023[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt1Gqt74%253D&md5=44d15c7a989af6b8b0d4ea22dda216dfKlotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney diseaseLin, Wenjun; Zhang, Qin; Liu, Lin; Yin, Shasha; Liu, Zhihong; Cao, WangsenKidney International (2017), 92 (3), 669-679CODEN: KDYIA5; ISSN:0085-2538. (Elsevier Inc.)Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho (1) expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A-induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the redn. of CKD progression.
- 253Zwinderman, M. R. H.; de Weerd, S.; Dekker, F. J. Targeting HDAC Complexes in Asthma and COPD. Epigenomes 2019, 3, 19, DOI: 10.3390/epigenomes3030019[Crossref], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFyr&md5=797188345106298228cf9cd061721ff3Targeting HDAC complexes in asthma and COPDZwinderman, Martijn R. H.; de Weerd, Sander; Dekker, Frank J.Epigenomes (2019), 3 (3), 19CODEN: EPIGD8; ISSN:2075-4655. (MDPI AG)A review. Around three million patients die due to airway inflammatory diseases each year. The most notable of these diseases are asthma and chronic obstructive pulmonary disease (COPD). Therefore, new therapies are urgently needed. Promising targets are histone deacetylases (HDACs), since they regulate posttranslational protein acetylation. Over a thousand proteins are reversibly acetylated, and acetylation critically influences aberrant intracellular signaling pathways in asthma and COPD. The diverse set of selective and non-selective HDAC inhibitors used in pre-clin. models of airway inflammation show promising results, but several challenges still need to be overcome. One such challenge is the design of HDAC inhibitors with unique selectivity profiles, such as selectivity towards specific HDAC complexes. Novel strategies to disrupt HDAC complexes should be developed to validate HDACs further as targets for new anti-inflammatory pulmonary treatments.
- 254Bougdour, A.; Maubon, D.; Baldacci, P.; Ortet, P.; Bastien, O.; Bouillon, A.; Barale, J. C.; Pelloux, H.; Ménard, R.; Hakimi, M. A. Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. J. Exp. Med. 2009, 206, 953– 966, DOI: 10.1084/jem.20082826[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvVSiu7c%253D&md5=67adb9644c32d6e568fc64685394fe75Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasitesBougdour, Alexandre; Maubon, Daniele; Baldacci, Patricia; Ortet, Philippe; Bastien, Olivier; Bouillon, Anthony; Barale, Jean-Christophe; Pelloux, Herve; Menard, Robert; Hakimi, Mohamed-AliJournal of Experimental Medicine (2009), 206 (4), 953-966CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although little is yet known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. We investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase inhibitor (HDACi). We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi's such as trichostatin A and the clin. relevant compd. pyrimethamine. We identify T. gondii HDAC3 (TgHDAC3) as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (nonreplicative) stage. Addnl., via its anti-TgHDAC3 activity, FR235222 influences the expression of ∼370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDACi of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and, likely, other Apicomplexa.
- 255Zhou, Y.; Wang, Q.; Yang, Q.; Tang, J.; Xu, C.; Gai, D.; Chen, X.; Chen, J. Histone deacetylase 3 inhibitor suppresses hepatitis C virus replication by regulating Apo-A1 and LEAP-1 expression. Virol. Sin. 2018, 33, 418– 428, DOI: 10.1007/s12250-018-0057-7[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKjt7bI&md5=439a3b8dc0e7c0fa854ef4c996883911Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 ExpressionZhou, Yuan; Wang, Qian; Yang, Qi; Tang, Jielin; Xu, Chonghui; Gai, Dongwei; Chen, Xinwen; Chen, JizhengVirologica Sinica (2018), 33 (5), 418-428CODEN: VSIICH; ISSN:1674-0769. (Springer GmbH)Histone deacetylase (HDAC) inhibitors show clin. promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concns. below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as detd. by microarray and quant. RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein α (C/EBPα), hypoxia-inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases assocd. with HCV infection such as HCC.
- 256Villanueva, R.; Iglesias, A. H.; Camelo, S.; Sanin, L. C.; Gray, S. G.; Dangond, F. Histone deacetylase 3 represses HTLV-1 tax transcription. Oncol. Rep. 2006, 16, 581– 585, DOI: 10.3892/or.16.3.581[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVagsLs%253D&md5=d1e7cff1fd10d1afe83e4e22d65def2eHistone deacetylase 3 represses HTLV-1 tax transcriptionVillanueva, Raul; Iglesias, Antonio H.; Camelo, Sandra; Sanin, Luis C.; Gray, Steven G.; Dangond, FernandoOncology Reports (2006), 16 (3), 581-585CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)We examd. the epigenetic mechanisms involved in human T-cell lymphotropic virus type 1 (HTLV-1) Tax expression. Blockade of histone deacetylation with trichostatin A (TSA) resulted in Tax upregulation. Using a chromatin immunopptn. (ChIP) assay, we verified local histone hyperacetylation at the HTLV-1 LTR in response to TSA. In agreement, HDAC3 transfection led to redns. in both Tax expression and histone acetylation. HDAC3 mutations and deletions spanning the catalytic site had variable ability to repress Tax, but HDAC activity was not essential for repression. Immunopptn. studies revealed that Tax co-exists in a complex contg. both histone deacetylase 1 (HDAC1) and 3 (HDAC3). Our results suggest that HDACs may actively participate in the repression of HTLV-1 Tax transcription.
- 257Barton, K. M.; Archin, N. M.; Keedy, K. S.; Espeseth, A. S.; Zhang, Y. L.; Gale, J.; Wagner, F. F.; Holson, E. B.; Margolis, D. M. Selective HDAC inhibition for the disruption of latent HIV-1 infection. PLoS One 2014, 9, e102684 DOI: 10.1371/journal.pone.0102684[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1CisrbM&md5=d967dbe2a9b6004029ded4b8cad2f657Selective HDAC inhibition for the disruption of latent HIV-1 infectionBarton, Kirston M.; Archin, Nancie M.; Keedy, Kara S.; Espeseth, Amy S.; Zhang, Yan-Ling; Gale, Jennifer; Wagner, Florence F.; Holson, Edward B.; Margolis, David M.PLoS One (2014), 9 (8), e102684/1-e102684/11, 11 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small mol. inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small mol. HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymic inhibition of HDAC3 with the selective small-mol. inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.
- 258Choudhary, V.; Olala, L. O.; Kagha, K.; Pan, Z. Q.; Chen, X.; Yang, R.; Cline, A.; Helwa, I.; Marshall, L.; Kaddour-Djebbar, I.; McGee-Lawrence, M. E.; Bollag, W. B. Regulation of the glycerol transporter, Aquaporin-3, by histone deacetylase-3 and p53 in keratinocytes. J. Invest. Dermatol. 2017, 137, 1935– 1944, DOI: 10.1016/j.jid.2017.04.031[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1WgurbM&md5=731c8746e34108da3f8c3044181d73e5Regulation of the Glycerol Transporter, Aquaporin-3, by Histone Deacetylase-3 and p53 in KeratinocytesChoudhary, Vivek; Olala, Lawrence O.; Kagha, Karen; Pan, Zhi-qiang; Chen, Xunsheng; Yang, Rong; Cline, Abigail; Helwa, Inas; Marshall, Lauren; Kaddour-Djebbar, Ismail; McGee-Lawrence, Meghan E.; Bollag, Wendy B.Journal of Investigative Dermatology (2017), 137 (9), 1935-1944CODEN: JIDEAE; ISSN:0022-202X. (Elsevier Inc.)Aquaporin- (AQP) 3, a water and glycerol channel, plays an important role in epidermal function, with studies showing its involvement in keratinocyte proliferation, differentiation, and migration and in epidermal wound healing and barrier repair. Increasing speculation about the use of histone deacetylase (HDAC) inhibitors to treat skin diseases led us to investigate HDAC's role in the regulation of AQP3. The broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid induced AQP3 mRNA and protein expression in a dose- and time-dependent manner in normal keratinocytes. The SAHA-induced increase in AQP3 levels resulted in enhanced [3H]glycerol uptake in normal but not in AQP3-knockout keratinocytes, confirming that the expressed AQP3 was functional. Use of HDAC inhibitors with different specificities limited our exploration of the responsible HDAC member to HDAC1, HDAC2, or HDAC3. Cre-recombinase-mediated knockdown and overexpression of HDAC3 suggested a role for HDAC3 in suppressing AQP3 expression basally. Further investigation implicated p53 as a transcription factor involved in regulating HDAC inhibitor-induced AQP3 expression. Thus, our study supports the regulation of AQP3 expression by HDAC3 and p53. Because suberoylanilide hydroxamic acid is already approved to treat cutaneous T-cell lymphoma, it could potentially be used as a therapy for skin diseases like psoriasis, where AQP3 is abnormally expressed.
- 259Kim, Y.; Kim, K.; Park, D.; Lee, E.; Lee, H.; Lee, Y. S.; Choe, J.; Jeoung, D. Histone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 protein. J. Biol. Chem. 2012, 287, 25844– 25859, DOI: 10.1074/jbc.M112.348284[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2ns7vL&md5=b0858b39b22e4acbe5e56be06de1670aHistone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 proteinKim, Youngmi; Kim, Kyungjong; Park, Deokbum; Lee, Eunmi; Lee, Hansoo; Lee, Yun-Sil; Choe, Jongseon; Jeoung, DooilJournal of Biological Chemistry (2012), 287 (31), 25844-25859CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have shown the induction of histone deacetylase 3 (HDAC3) in antigen-stimulated rat basophilic leukemia cells via NF-κB. We investigated the role of HDAC3 in allergic skin inflammation. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. Triphasic cutaneous reaction involved induction of HDAC3 and was mediated by HDAC3. HDAC3 showed an interaction with FcεRIβ. Trichostatin A (TSA), an inhibitor of HDAC(s), disrupted this interaction. Cytokine array anal. showed that the down-regulation of HDAC3 led to the decreased secretion of monocyte chemoattractant protein 1 (MCP1). FcεRI was necessary for induction of HDAC3 and MCP1. ChIP assays showed that HDAC3, in assocn. with Sp1 and c-Jun, was responsible for induction of MCP1 expression. TSA exerted a neg. effect on induction of MCP1. HDAC3 exerted a neg. regulation on expression of HDAC2 via interaction with Rac1. The down-regulation of HDAC3 or inactivation of Rac1 induced binding of HDAC2 to MCP1 promoter sequences. TSA exerted a neg. effect on HDAC3-mediated TpCR. The BALB/c mouse model of PCA involved induction of HDAC3 and MCP1. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Recombinant MCP1 enhanced β-hexosaminidase activity and histamine release and also showed angiogenic potential. TSA exerted a neg. effect on PCA. Our data show HDAC3 as a valuable target for the development of allergic skin inflammation therapeutics.
- 260Kim, Y.; Kim, K.; Park, D.; Lee, E.; Lee, H.; Lee, Y. S.; Choe, J.; Kim, Y. M.; Jeoung, D. DNA methyl transferase I acts as a negative regulator of allergic skin inflammation. Mol. Immunol. 2013, 53, 1– 14, DOI: 10.1016/j.molimm.2012.06.010[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlaiurfP&md5=143c3a50810d410f6e498c6ca9240949DNA methyl transferase I acts as a negative regulator of allergic skin inflammationKim, Youngmi; Kim, Kyungjong; Park, Deokbum; Lee, Eunmi; Lee, Hansoo; Lee, Yun-Sil; Choe, Jongseon; Kim, Young-Myeong; Jeoung, DooilMolecular Immunology (2013), 53 (1-2), 1-14CODEN: MOIMD5; ISSN:0161-5890. (Elsevier)The role of DNA Me transferase I (DNMT1) in allergic inflammation was investigated. Antigen stimulation decreased expression of DNMT1 in rat basophilic leukemia cells (RBL2H3). The down regulation of DNMT1 induced expression of histone deacetylase 3 (HDAC3). HDAC3 was necessary for allergic skin inflammation, such as such as triphasic cutaneous reaction and passive cutaneous anaphylaxis. The down regulation of DNMT1 resulted from activation of PKC and rac1 which were necessary for proteasome-dependent ubiquitination of DNMT1 by antigen stimulation. N-acetyl-L-cysteine, an inhibitor of reactive oxygen species prodn., exerted neg. effects on allergic skin inflammation. Antigen stimulation led to increased expression of Tip60, a histone acetyl transferase. Wild type, but not mutant form, Tip60 decreased expression of DNMT1 while increasing expression of HDAC3, suggesting role for acetylation in ubiquitin-dependent proteasomal degrdn. of DNMT1. In vivo down regulation of DNMT1 increased ear thickness, typical of allergic skin inflammation, induced vascular leakage and promoted angiogenesis in BALB/c mouse. The down regulation of DNMT1 enhanced angiogenic potential of rat aortic endothelial cells (RAEC) accompanied by activation of VEGFR-2 and induced interaction between VEGFR-2 and syk in RAEC. The enhanced angiogenic potential of RAEC was assocd. with the induction of VEGF by down regulation of DNMT1 in RBL2H3 cells. The down regulation of DNMT1 induced leukocytes-endothelial cell interaction and expression of various adhesion mols. Aspirin exerted a neg. effect on allergic skin inflammation by indirect regulation on DNMT1 via Tip60. Taken together, these results suggest novel role for DNMT1 in allergic skin inflammation.
- 261Kim, Y.; Eom, S.; Kim, K.; Lee, Y. S.; Choe, J.; Hahn, J. H.; Lee, H.; Kim, Y. M.; Ha, K. S.; Ro, J. Y.; Jeoung, D. Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammation. Mol. Immunol. 2010, 47, 1010– 1022, DOI: 10.1016/j.molimm.2009.11.017[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFKrtw%253D%253D&md5=4828dda2d1152af6c55dd1d462cf6784Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammationKim, Youngmi; Eom, Sangkyung; Kim, Kyungjong; Lee, Yun-Sil; Choe, Jongseon; Hahn, Jang Hee; Lee, Hansoo; Kim, Young-Myeong; Ha, Kwon Soo; Ro, Jai Youl; Jeoung, DooilMolecular Immunology (2010), 47 (5), 1010-1022CODEN: MOIMD5; ISSN:0161-5890. (Elsevier Ltd.)Transglutaminase II (TGase II) is a protein crosslinking enzyme with diverse biol. functions. Here the authors report the role of TGase II in allergic inflammation. Antigen stimulation induced expression and activity of TGase II by activation of NF-κB in rat basophilic leukemia (RBL2H3) cells. This induction of TGase II was dependent on FcεRI and EGFR. Interaction between TGase II and rac1 was induced following antigen stimulation. TGase II was responsible for the increased prodn. of reactive oxygen species, expression of prostaglandin E2 synthase (PGE2 synthase) and was responsible for increased secretion of prostaglandin E2. ChIP assay showed that TGase II, through interaction with NF-κB, was responsible for the induction of histone deacetylase-3 (HDAC3) and snail by direct binding to promoter sequences. HDAC3 and snail induced by TGase II, exerted transcriptional repression on E-cadherin. Snail exerted neg. effect on expression of MMP-2, and secretion of Th2 cytokines. Inhibition of matrix metalloproteinase-2 (MMP-2) inhibited secretion of Th2 cytokines. In vivo induction of TGase II was obsd. in Balb/c mouse model of IgE antibody-induced passive cutaneous anaphylaxis. Chem. inhibition of TGase II exerted neg. effect on IgE-dependent passive cutaneous anaphylaxis. Chem. inhibition of TGase II by cystamine exerted neg. effect on Balb/c mouse model of phorbol myristate acetate (PMA)-induced atopic dermatitis. These results suggest novel role of TGase II in allergic inflammation and TGase II can be developed as target for the development of allergy therapeutics.
- 262Shu, J.; Li, L.; Zhou, L. B.; Qian, J.; Fan, Z. D.; Zhuang, L. L.; Wang, L. L.; Jin, R.; Yu, H. G.; Zhou, G. P. IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors. Oncotarget 2017, 8, 47184– 47194, DOI: 10.18632/oncotarget.17586[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crptlymsg%253D%253D&md5=b4eda1d9e7bf2e20c0b2e1b9beef5794IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitorsShu Jin; Li Ling; Qian Jun; Zhou Lan-Bo; Fan Zhi-Dan; Yu Hai-Guo; Zhuang Li-Li; Wang Lu-Lu; Jin Rui; Zhou Guo-PingOncotarget (2017), 8 (29), 47184-47194 ISSN:.Interferon regulatory factor 5 (IRF5) plays a critical role in the induction of type I interferon, proinflammatory cytokines and chemokines, and participates in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, the relationship between IRF5 and childhood-onset SLE remains elusive. In the present study, we demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative real-time PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5. In addition to being used as antitumor drugs, a number of histone deacetylase inhibitors (HDACi) display potent anti-inflammatory properties; however, their effects on IRF5 expression remain unclear. In this study, we identified that HDACi trichostatin A (TSA) and histone acetyltransferase (HAT)-p300 downregulated IRF5 promoter activity, mRNA expression, and protein level, whereas the HAT-p300/CBP-associated factor had no effect. Moreover, TSA inhibited the production of TNF-α and IL-6 in differentiated THP-1cells. Furthermore, chromatin immunoprecipitation assays revealed that TSA inhibited DNA binding of Sp1, RNA polymerase II, HDAC3, and p300 to the core promoter region of IRF5. Our results suggest that HDACi may have therapeutic potential in patients with autoimmune diseases such as SLE through repression of IRF5 expression.
- 263Hannan, J. L.; Kutlu, O.; Stopak, B. L.; Liu, X.; Castiglione, F.; Hedlund, P.; Burnett, A. L.; Bivalacqua, T. J. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J. Sex. Med. 2014, 11, 1442– 1451, DOI: 10.1111/jsm.12522[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Wjs74%253D&md5=01fa374d516b0cac34faef280bb529bcValproic Acid Prevents Penile Fibrosis and Erectile Dysfunction in Cavernous Nerve-Injured RatsHannan, Johanna L.; Kutlu, Omer; Stopak, Bernard L.; Liu, Xiaopu; Castiglione, Fabio; Hedlund, Petter; Burnett, Arthur L.; Bivalacqua, Trinity J.Journal of Sexual Medicine (2014), 11 (6), 1442-1451CODEN: JSMOAN; ISSN:1743-6095. (Wiley-Blackwell)Introduction : Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims : This study will characterize the mol. changes in penile HDAC after BCNI and det. if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods : Five groups of rats (8-10 wk, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to det. intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-β1 (TGF-β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were detd. in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α-SMA) antibodies. Main Outcome Measures : We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-β1 protein expression; penile fibrosis; penile α-SMA content. Results : There was a voltage-dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF-β1 protein expression after BCNI. Histol. anal. showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α-SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (P < 0.05). Conclusion : HDAC-induced pathol. signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacol. inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy. Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, Burnett AL, and Bivalacqua TJ. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats.
- 264Tapadar, S.; He, R.; Luchini, D. N.; Billadeau, D. D.; Kozikowski, A. P. Isoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: effects on HDAC biology and antiproliferative activity. Bioorg. Med. Chem. Lett. 2009, 19, 3023– 3026, DOI: 10.1016/j.bmcl.2009.04.058[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVersrs%253D&md5=affc37e7890fc939db595fa48397390cIsoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: Effects on HDAC biology and antiproliferative activityTapadar, Subhasish; He, Rong; Luchini, Doris N.; Billadeau, Daniel D.; Kozikowski, Alan P.Bioorganic & Medicinal Chemistry Letters (2009), 19 (11), 3023-3026CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of hydroxamic acid based histone deacetylase inhibitors 6-15, contg. an isoxazole moiety adjacent to the Zn-chelating hydroxamic acid, is reported herein. Some of these compds. showed nanomolar activity in the HDAC isoform inhibitory assay and exhibited micromolar inhibitory activity against five pancreatic cancer cell lines.
- 265Neelarapu, R.; Holzle, D. L.; Velaparthi, S.; Bai, H.; Brunsteiner, M.; Blond, S. Y.; Petukhov, P. A. Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes. J. Med. Chem. 2011, 54, 4350– 4364, DOI: 10.1021/jm2001025[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntVemsbw%253D&md5=274a01467ab7108b87dd6634562f4635Design, Synthesis, Docking, and Biological Evaluation of Novel Diazide-Containing Isoxazole- and Pyrazole-Based Histone Deacetylase ProbesNeelarapu, Raghupathi; Holzle, Denise L.; Velaparthi, Subash; Bai, He; Brunsteiner, Michael; Blond, Sylvie Y.; Petukhov, Pavel A.Journal of Medicinal Chemistry (2011), 54 (13), 4350-4364CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design, synthesis, docking, and biol. evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) expts. in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, resp. The pyrazole-based probe I appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC50 of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors II, III (R = H, N3) and I exerted the antiproliferative and neuroprotective activities at micromolar concns. through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.
- 266Thaler, F.; Varasi, M.; Abate, A.; Carenzi, G.; Colombo, A.; Bigogno, C.; Boggio, R.; Zuffo, R. D.; Rapetti, D.; Resconi, A.; Regalia, N.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C. Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors. Eur. J. Med. Chem. 2013, 64, 273– 284, DOI: 10.1016/j.ejmech.2013.03.061[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptFOntbs%253D&md5=3269d95992f1ede24d84b185624f04d6Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitorsThaler, Florian; Varasi, Mario; Abate, Agnese; Carenzi, Giacomo; Colombo, Andrea; Bigogno, Chiara; Boggio, Roberto; Dal Zuffo, Roberto; Rapetti, Daniela; Resconi, Anna; Regalia, Nickolas; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, CiroEuropean Journal of Medicinal Chemistry (2013), 64 (), 273-284CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Histone deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies the authors described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, the authors report further explorations, which resulted in the discovery of a new class of spiro-benzoxazinepiperidines I [R = H, Me, Bn, etc., R1 = H, Me, Bn]. Several compds. showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumor cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumor growth inhibition. In addn., the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogs.
- 267Thaler, F.; Varasi, M.; Carenzi, G.; Colombo, A.; Abate, A.; Bigogno, C.; Boggio, R.; Carrara, S.; Cataudella, T.; Dal Zuffo, R.; Reali, V.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C. ChemMedChem 2012, 7, 709– 721, DOI: 10.1002/cmdc.201200024[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFyis7w%253D&md5=b1a34d6dfb56c2919cd560f64acb726aSpiro[chromane-2,4'-piperidine]-Based Histone Deacetylase Inhibitors with Improved in vivo ActivityThaler, Florian; Varasi, Mario; Carenzi, Giacomo; Colombo, Andrea; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carrara, Simone; Cataudella, Tiziana; Dal Zuffo, Roberto; Reali, Veronica; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, CiroChemMedChem (2012), 7 (4), 709-721CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of spiro[chromane-2,4'-piperidine] derivs. based on a previously published lead benzyl spirocycle (I) and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepd. as novel histone deacetylase (HDAC) inhibitors. The compds. were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compds. exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after i.v. and oral administration than spiropiperidine (I) under the conditions used. The improved PK behavior of these two compds. also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.
- 268Thaler, F.; Moretti, L.; Amici, R.; Abate, A.; Colombo, A.; Carenzi, G.; Fulco, M. C.; Boggio, R.; Dondio, G.; Gagliardi, S.; Minucci, S.; Sartori, L.; Varasi, M.; Mercurio, C. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. Eur. J. Med. Chem. 2016, 108, 53– 67, DOI: 10.1016/j.ejmech.2015.11.010[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFantLjK&md5=1433be1e457ff6227bc42bec6241b974Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitorsThaler, Florian; Moretti, Loris; Amici, Raffaella; Abate, Agnese; Colombo, Andrea; Carenzi, Giacomo; Fulco, Maria Carmela; Boggio, Roberto; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Sartori, Luca; Varasi, Mario; Mercurio, CiroEuropean Journal of Medicinal Chemistry (2016), 108 (), 53-67CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivs. able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivs., e.g., I, by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compds. with a good in vitro ADME profile. In addn., mol. modeling studies unravelled the binding mode of these inhibitors.
- 269Choi, C. J.; Kim, M.; Han, S. Y.; Jeon, J.; Lee, J. H.; Oh, J. I.; Suh, K. H.; Suh, D. C.; Lee, K. O. Discovery of a Novel HDAC3 selective inhibitor and its evaluation in lymphoma model. Bull. Korean Chem. Soc. 2016, 37, 42– 47, DOI: 10.1002/bkcs.10619[Crossref], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVCltL3O&md5=f439ffafc6f8468139355fbf46606434Discovery of a Novel HDAC3 Selective Inhibitor and its Evaluation in Lymphoma ModelChoi, Chang-Ju; Kim, Mira; Han, Sun Young; Jeon, Jiyoung; Lee, Jae Ho; Oh, Jeong-In; Suh, Kwee Hyun; Suh, Dong-Churl; Lee, Kwang-OkBulletin of the Korean Chemical Society (2016), 37 (1), 42-47CODEN: BKCSDE; ISSN:0253-2964. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylase (HDAC) inhibition is a potentially attractive approach to cancer therapy. A no. of HDAC inhibitors are in clin. development stages for the treatment of cancer as well as immune and inflammatory disorders. Although there are several approved HDAC inhibitors by the US FDA, they show a broad inhibitory spectrum against HDAC subfamily. Herein, we synthesized a series of novel hydroxamate analogs, and evaluated them with lymphoma cancer cell. Conclusively, we identified an HDAC3 selective inhibitor which shows good anticancer activity for the lymphoma model, as well as a good drug metab. and pharmacokinetics (DMPK) profile.
- 270Zang, J.; Shi, B.; Liang, X.; Gao, Q.; Xu, W.; Zhang, Y. Development of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activity. Bioorg. Med. Chem. 2017, 25, 2666– 2675, DOI: 10.1016/j.bmc.2016.12.001[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVSlur8%253D&md5=8ce20c262f96079fa20d9e48ddc02a3bDevelopment of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activityZang, Jie; Shi, Baowen; Liang, Xuewu; Gao, Qianwen; Xu, Wenfang; Zhang, YingjieBioorganic & Medicinal Chemistry (2017), 25 (9), 2666-2675CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compds. Most compds. showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compd. 1 and even the pos. control SAHA. What's more, compared with the approved HDACs inhibitor SAHA, compds. 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compd. 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N-hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compds.
- 271Cheng, G.; Wang, Z.; Yang, J.; Bao, Y.; Xu, Q.; Zhao, L.; Liu, D. Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents. Bioorg. Chem. 2019, 84, 410– 417, DOI: 10.1016/j.bioorg.2018.12.011[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFaqtb%252FI&md5=e2c81b5d67fd9f49e6805c6b544438b4Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agentsCheng, Gaoliang; Wang, Zhi; Yang, Jinyu; Bao, Yu; Xu, Qihao; Zhao, Linxiang; Liu, DanBioorganic Chemistry (2019), 84 (), 410-417CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivs. that combine the inhibitory activities of BRD4 and HDAC into one mol. were designed and synthesized through the structure-based design method. Most compds. showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compds. were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC50 value of 5 nM and BRD4 inhibition rate of 88% at 10 μM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot anal. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.
- 272Chen, Y.; He, R.; Chen, Y.; D’Annibale, M. A.; Langley, B.; Kozikowski, A. P. Studies of benzamide- and thiol-based histone deacetylase inhibitors in models of oxidative-stress-induced neuronal death: identification of some HDAC3-selective inhibitors. ChemMedChem 2009, 4, 842– 852, DOI: 10.1002/cmdc.200800461[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1KgsbY%253D&md5=38ef2bc8efbc71d2d5b6d195da49c35dStudies of Benzamide- and Thiol-Based Histone Deacetylase Inhibitors in Models of Oxidative-Stress-Induced Neuronal Death: Identification of Some HDAC3-Selective InhibitorsChen, Yufeng; He, Rong; Chen, Yihua; D'Annibale, Melissa A.; Langley, Brett; Kozikowski, Alan P.ChemMedChem (2009), 4 (5), 842-852CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Less stress: We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide-based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA-cortical neuron model of oxidative stress. We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. This study reveals that none of the benzamide-based HDAC inhibitors (HDACIs) provides any neuroprotection whatsoever, in distinct contrast to HDACIs that contain other ZBGs. Some of the sulfur-contg. HDACIs, namely the thiols, thioesters, and disulfides present modest neuroprotective activity but show toxicity at higher concns. Taken together, these data demonstrate that the HDAC6-selective mercaptoacetamides that were reported previously provide the best protection in the homocysteic acid model of oxidative stress, thus further supporting their study in animal models of neurodegenerative diseases.
- 273He, R.; Chen, Y.; Chen, Y.; Ougolkov, A. V.; Zhang, J. S.; Savoy, D. N.; Billadeau, D. D.; Kozikowski, A. P. Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents. J. Med. Chem. 2010, 53, 1347– 1356, DOI: 10.1021/jm901667k[ACS Full Text], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvVGqug%253D%253D&md5=80c55a4aa2fd3cb5b440ff34aec02b7cSynthesis and Biological Evaluation of Triazol-4-ylphenyl-Bearing Histone Deacetylase Inhibitors as Anticancer AgentsHe, Rong; Chen, Yufeng; Chen, Yihua; Ougolkov, Andrei V.; Zhang, Jin-San; Savoy, Doris N.; Billadeau, Daniel D.; Kozikowski, Alan P.Journal of Medicinal Chemistry (2010), 53 (3), 1347-1356CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC50 value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogs by embellishing the terminal Ph ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogs was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compds. 4h (I) and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC50 = 50 nM) and MiaPaca-2 (IC50 = 40 nM) cancer cell lines, resp. Compd. 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
- 274Boissinot, M.; Inman, M.; Hempshall, A.; James, S. R.; Gill, J. H.; Selby, P.; Bowen, D. T.; Grigg, R.; Cockerill, P. N. Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192. Leuk. Res. 2012, 36, 1304– 1310, DOI: 10.1016/j.leukres.2012.07.002[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2it7%252FJ&md5=3cd7587d757dcb74b99c10df0122dd63Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192Boissinot, Marjorie; Inman, Martyn; Hempshall, Aiden; James, Sally R.; Gill, Jason H.; Selby, Peter; Bowen, David T.; Grigg, Ronald; Cockerill, Peter N.Leukemia Research (2012), 36 (10), 1304-1310CODEN: LEREDD; ISSN:0145-2126. (Elsevier Ltd.)Histone deacetylase inhibitors (HDACIs) are in advanced clin. development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliph. compds. with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clin. trials, such as the benzamide group compds. MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compd. named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukemic origin. When tested in culture against the acute myeloid leukemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukemia.
- 275Suzuki, T.; Kasuya, Y.; Itoh, Y.; Ota, Y.; Zhan, P.; Asamitsu, K.; Nakagawa, H.; Okamoto, T.; Miyata, N. Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. PLoS One 2013, 8, e68669 DOI: 10.1371/journal.pone.0068669[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SgsrjF&md5=74d12c8fb1f06f8e00691415434fd929Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assemblySuzuki, Takayoshi; Kasuya, Yuki; Itoh, Yukihiro; Ota, Yosuke; Zhan, Peng; Asamitsu, Kaori; Nakagawa, Hidehiko; Okamoto, Takashi; Miyata, NaokiPLoS One (2013), 8 (7), e68669CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chem.", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isoenzymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compds. showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isoenzymes. Compds. T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addn., these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chem. approach to find isoenzyme-selective HDAC inhibitors.
- 276Marson, C. M.; Matthews, C. J.; Yiannaki, E.; Atkinson, S. J.; Soden, P. E.; Shukla, L.; Lamadema, N.; Thomas, N. S. Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit. J. Med. Chem. 2013, 56, 6156– 6174, DOI: 10.1021/jm400634n[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKitrfE&md5=afca61205f7bfeb7c33006df41e61737Discovery of Potent, Isoform-Selective Inhibitors of Histone Deacetylase Containing Chiral Heterocyclic Capping Groups and a N-(2-Aminophenyl)benzamide Binding UnitMarson, Charles M.; Matthews, Christopher J.; Yiannaki, Elena; Atkinson, Stephen J.; Soden, Peter E.; Shukla, Lena; Lamadema, Nermina; Thomas, N. Shaun B.Journal of Medicinal Chemistry (2013), 56 (15), 6156-6174CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide I gave resp. IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by I was obsd., with resp. IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
- 277Marson, C. M.; Matthews, C. J.; Atkinson, S. J.; Lamadema, N.; Thomas, N. S. Potent and selective inhibitors of histone deacetylase-3 containing chiral oxazoline capping groups and a N-(2-Aminophenyl)-benzamide binding unit. J. Med. Chem. 2015, 58, 6803– 6818, DOI: 10.1021/acs.jmedchem.5b00545[ACS Full Text], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOjur%252FO&md5=9a6fa3c009c84296988f194e1f958ee1Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding UnitMarson, Charles M.; Matthews, Christopher J.; Atkinson, Stephen J.; Lamadema, Nermina; Thomas, N. Shaun B.Journal of Medicinal Chemistry (2015), 58 (17), 6803-6818CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide I gave resp. IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of I. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was obsd. for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
- 278Li, X.; Zhang, Y.; Jiang, Y.; Wu, J.; Inks, E. S.; Chou, C. J.; Gao, S.; Hou, J.; Ding, Q.; Li, J.; Wang, X.; Huang, Y.; Xu, W. Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study. Eur. J. Med. Chem. 2017, 134, 185– 206, DOI: 10.1016/j.ejmech.2017.03.069[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFWnt70%253D&md5=66ad0ddda5b3e46ef07dfb40951b63dbSelective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity studyLi, Xiaoyang; Zhang, Yingjie; Jiang, Yuqi; Wu, Jingde; Inks, Elizabeth S.; Chou, C. James; Gao, Shuai; Hou, Jinning; Ding, Qinge; Li, Jingyao; Wang, Xue; Huang, Yongxue; Xu, WenfangEuropean Journal of Medicinal Chemistry (2017), 134 (), 185-206CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compd. 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compds. exhibited high HDACs inhibitory potency. Compd. 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In vivo studies revealed that compd. 11a displayed potent oral antitumor activity in both hematol. tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and Ph compds. (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine contg. compd. 56, with moderate HDAC3 selectivity.
- 279Hsieh, H. Y.; Chuang, H. C.; Shen, F. H.; Detroja, K.; Hsin, L. W.; Chen, C. S. Targeting breast cancer stem cells by novel HDAC3-selective inhibitors. Eur. J. Med. Chem. 2017, 140, 42– 51, DOI: 10.1016/j.ejmech.2017.08.069[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFWnsbnL&md5=a0ad5d8e018d7471975602be2ba238ebTargeting breast cancer stem cells by novel HDAC3-selective inhibitorsHsieh, Hao-Yu; Chuang, Hsiao-Ching; Shen, Fang-Hsiu; Detroja, Kinjal; Hsin, Ling-Wei; Chen, Ching-ShihEuropean Journal of Medicinal Chemistry (2017), 140 (), 42-51CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-neg. breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivs. exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the down regulation of β-catenin.
- 280McClure, J. J.; Inks, E. S.; Zhang, C.; Peterson, Y. K.; Li, J.; Chundru, K.; Lee, B.; Buchanan, A.; Miao, S.; Chou, C. J. Comparison of the deacylase and deacetylase activity of zinc-dependent HDACs. ACS Chem. Biol. 2017, 12, 1644– 1655, DOI: 10.1021/acschembio.7b00321[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVent7w%253D&md5=7e6a761d303149a0367afbbe5a019d80Comparison of the deacylase and deacetylase activity of zinc-dependent HDACsMcClure, Jesse J.; Inks, Elizabeth S.; Zhang, Cheng; Peterson, Yuri K.; Li, Jiaying; Chundru, Kalyan; Lee, Bradley; Buchanan, Ashley; Miao, Shiqin; Chou, C. JamesACS Chemical Biology (2017), 12 (6), 1644-1655CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)The acetylation status of lysine residues on histone proteins has long been attributed to a balance struck between the catalytic activity of histone acetyl transferases and histone deacetylases (HDAC). HDACs were identified as the sole removers of acetyl post-translational modifications (PTM) of histone lysine residues. Studies into the biol. role of HDACs have also elucidated their role as removers of acetyl PTMs from lysine residues of nonhistone proteins. These findings, coupled with high-resoln. mass spectrometry studies that revealed the presence of acyl-group PTMs on lysine residues of nonhistone proteins, brought forth the possibility of HDACs acting as removers of both acyl- and acetyl-based PTMs. We posited that HDACs fulfill this dual role and sought to investigate their specificity. Utilizing a fluorescence-based assay and biol. relevant acyl-substrates, the selectivities of zinc-dependent HDACs toward these acyl-based PTMs were identified. These findings were further validated using cellular models and mol. biol. techniques. As a proof of principal, an HDAC3 selective inhibitor was designed using HDAC3's substrate preference. This resulting inhibitor demonstrates nanomolar activity and >30 fold selectivity toward HDAC3 compared to the other class I HDACs. This inhibitor is capable of increasing p65 acetylation, attenuating NF-κB activation, and thereby preventing downstream nitric oxide signaling. Addnl., this selective HDAC3 inhibition allows for control of HMGB-1 secretion from activated macrophages without altering the acetylation status of histones or tubulin.
- 281Ocasio, C. A.; Sansook, S.; Jones, R.; Roberts, J. M.; Scott, T. G.; Tsoureas, N.; Coxhead, P.; Guille, M.; Tizzard, G. J.; Coles, S. J.; Hochegger, H.; Bradner, J. E.; Spencer, J. Pojamide: An HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells. Organometallics 2017, 36, 3276– 3283, DOI: 10.1021/acs.organomet.7b00437[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlGhtr%252FM&md5=ce4c27bec86738e1c618c9eb5c8cba70Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in CellsOcasio, Cory A.; Sansook, Supojjanee; Jones, Rhiannon; Roberts, Justin M.; Scott, Thomas G.; Tsoureas, Nikolaos; Coxhead, Peter; Guille, Matthew; Tizzard, Graham J.; Coles, Simon J.; Hochegger, Helfrid; Bradner, James E.; Spencer, JohnOrganometallics (2017), 36 (17), 3276-3283CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)A ferrocene contg. ortho-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide, 2b (Pojamide) displayed nanomolar potency vs. HDAC3. Compared to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and Romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC 1 and 3 inhibition is desirable to achieve max. anticancer benefits. Addnl., the authors explored Pojamide-induced redox-pharmacol. Indeed, treating HCT116 cells with Pojamide, SNP (Na nitroprusside) and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage attributed to activation to an Fe(III) species.
- 282Trivedi, P.; Adhikari, N.; Amin, S. A.; Jha, T.; Ghosh, B. Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects. Eur. J. Pharm. Sci. 2018, 124, 165– 181, DOI: 10.1016/j.ejps.2018.08.030[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1emtr7L&md5=b0e2696ed9abb37d574b22b1be36da90Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effectsTrivedi, Prakruti; Adhikari, Nilanjan; Amin, Sk. Abdul; Jha, Tarun; Ghosh, BalaramEuropean Journal of Pharmaceutical Sciences (2018), 124 (), 165-181CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A no. of HDAC inhibitors have been used pre-clin. and clin. as anticancer agents. In the current study, we have designed and synthesized compd. 12a by combining the scaffolds of CI-994 and BG45. Moreover, the structure of compd. 12a was optimized and a series of 2-aminobenzamide derivs. were synthesized further. These compds. were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compd. 26c showed 11.68-fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compds. exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compd. 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI-994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small mol. HDAC3 inhibitors to fight against the target specific malignancies in future.
- 283Cao, F.; de Weerd, S.; Chen, D.; Zwinderman, M. R. H.; van der Wouden, P. E.; Dekker, F. J. Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC). Eur. J. Med. Chem. 2020, 208, 112800, DOI: 10.1016/j.ejmech.2020.112800[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFSisbrI&md5=8e9bb1f170b924f07ef4186e9f6fdac4Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)Cao, Fangyuan; de Weerd, Sander; Chen, Deng; Zwinderman, Martijn R. H.; van der Wouden, Petra E.; Dekker, Frank J.European Journal of Medicinal Chemistry (2020), 208 (), 112800CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degrdn. of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degrdn. effects for HDAC3 with a DC50 value of 0.32 μM. In contrast to biochem. evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biol. outcome.
- 284McClure, J. J.; Zhang, C.; Inks, E. S.; Peterson, Y. K.; Li, J.; Chou, C. J. Development of allosteric hydrazide-containing Class I histone deacetylase inhibitors for use in acute myeloid leukemia. J. Med. Chem. 2016, 59, 9942– 9959, DOI: 10.1021/acs.jmedchem.6b01385[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12gtbrE&md5=52d5222010a0de3cfecde9a04c3efb84Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid LeukemiaMcClure, Jesse J.; Zhang, Cheng; Inks, Elizabeth S.; Peterson, Yuri K.; Li, Jiaying; Chou, C. JamesJournal of Medicinal Chemistry (2016), 59 (21), 9942-9959CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compds. contg. this motif require much higher dosing in clinic to achieve therapeutic concns. With the goal of developing a second generation of HDAC inhibitors, lacking this hydroxamate, the authors designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of the authors' lead analogs' efficacy, selectivity, and toxicity profiles demonstrate they possess low nanomolar activity against models of Acute Myeloid Leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells.
- 285Li, X.; Peterson, Y. K.; Inks, E. S.; Himes, R. A.; Li, J.; Zhang, Y.; Kong, X.; Chou, C. J. Class I HDAC inhibitors display different antitumor mechanism in leukemia and prostatic cancer cells depending on their p53 status. J. Med. Chem. 2018, 61, 2589– 2606, DOI: 10.1021/acs.jmedchem.8b00136[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjslKrs7w%253D&md5=36fcd594770688e5dcbbdbd3c8619b89Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 StatusLi, Xiaoyang; Peterson, Yuri K.; Inks, Elizabeth S.; Himes, Richard A.; Li, Jiaying; Zhang, Yingjie; Kong, Xiujie; Chou, C. JamesJournal of Medicinal Chemistry (2018), 61 (6), 2589-2603CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compd. I exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using II as a lead. Representative compd. 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compd. 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compd. 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.
- 286Li, X.; Jiang, Y.; Peterson, Y. K.; Xu, T.; Himes, R. A.; Luo, X.; Yin, G.; Inks, E. S.; Dolloff, N.; Halene, S.; Chan, S. S. L.; Chou, C. J. Design of hydrazide-bearing HDACIs based on panobinostat and their p53 and FLT3-ITD dependency in antileukemia activity. J. Med. Chem. 2020, 63, 5501– 5525, DOI: 10.1021/acs.jmedchem.0c00442[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnslShs7w%253D&md5=6be6aca92100a8e8ed437275c87f22c0Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia ActivityLi, Xiaoyang; Jiang, Yuqi; Peterson, Yuri K.; Xu, Tongqiang; Himes, Richard A.; Luo, Xin; Yin, Guilin; Inks, Elizabeth S.; Dolloff, Nathan; Halene, Stephanie; Chan, Sherine S. L.; Chou, C. JamesJournal of Medicinal Chemistry (2020), 63 (10), 5501-5525CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a(I) is incapable of causing apoptosis at a therapeutic concn. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degrdn. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and a higher AUC0-inf value.
- 287Xiao, Y.; Wang, J.; Zhao, L. Y.; Chen, X.; Zheng, G.; Zhang, X.; Liao, D. Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs. Chem. Commun. 2020, 56, 9866– 9869, DOI: 10.1039/D0CC03243C[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVaqurvL&md5=828f9a26ff7c3e7f8736d0c9fdd0a3beDiscovery of histone deacetylase 3 (HDAC3)-specific PROTACsXiao, Yufeng; Wang, Jia; Zhao, Lisa Y.; Chen, Xinyi; Zheng, Guangrong; Zhang, Xuan; Liao, DaiqingChemical Communications (Cambridge, United Kingdom) (2020), 56 (68), 9866-9869CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Histone deacetylases (HDACs) are validated drug targets for cancer treatment. Increased HDAC isoenzyme selectivity and novel strategies to inhibit HDAC activity could lead to safer and more effective drug candidates. Nonetheless, it is quite challenging to develop isoenzyme-specific HDACi due to the highly conserved catalytic domain. We discovered XZ9002, a first-in-class HDAC3-specific PROTAC that potently degraded HDAC3. Importantly, XZ9002 is more effective to inhibit cancer cell proliferation than its proteolysis-inactive counterpart, suggesting HDAC3 degrdn. is a novel and promising anticancer approach.
- 288Liu, J.; Yu, Y.; Kelly, J.; Sha, D.; Alhassan, A. B.; Yu, W.; Maletic, M. M.; Duffy, J. L.; Klein, D. J.; Holloway, M. K.; Carroll, S.; Howell, B. J.; Barnard, R. J. O.; Wolkenberg, S.; Kozlowski, J. A. Discovery of highly selective and potent HDAC3 inhibitors based on a 2-substituted benzamide zinc binding group. ACS Med. Chem. Lett. 2020, 11, 2476– 2483, DOI: 10.1021/acsmedchemlett.0c00462[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVeqsrrN&md5=fd3c45a5941acbc7876ac51e799b66acDiscovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding GroupLiu, Jian; Yu, Younong; Kelly, Joseph; Sha, Deyou; Alhassan, Abdul-Basit; Yu, Wensheng; Maletic, Milana M.; Duffy, Joseph L.; Klein, Daniel J.; Holloway, M. Katharine; Carroll, Steve; Howell, Bonnie J.; Barnard, Richard J. O.; Wolkenberg, Scott; Kozlowski, Joseph A.ACS Medicinal Chemistry Letters (2020), 11 (12), 2476-2483CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chem. (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series contg. 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compd. 16 with a 2-methylthiobenzamide. Compd. 16 inhibited HDAC3 with an IC50 of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compds. for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.
- 289Kinzel, O.; Llauger-Bufi, L.; Pescatore, G.; Rowley, M.; Schultz-Fademrecht, C.; Monteagudo, E.; Fonsi, M.; Gonzalez Paz, O.; Fiore, F.; Steinkühler, C.; Jones, P. Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties. J. Med. Chem. 2009, 52, 3453– 3456, DOI: 10.1021/jm9004303[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvFWnsb0%253D&md5=8674adc0c3892942a1fc7b154cbc84b4Discovery of a Potent Class I Selective Ketone Histone Deacetylase Inhibitor with Antitumor Activity in Vivo and Optimized Pharmacokinetic PropertiesKinzel, Olaf; Llauger-Bufi, Laura; Pescatore, Giovanna; Rowley, Michael; Schultz-Fademrecht, Carsten; Monteagudo, Edith; Fonsi, Massimiliano; Gonzalez Paz, Odalys; Fiore, Fabrizio; Steinkuhler, Christian; Jones, PhilipJournal of Medicinal Chemistry (2009), 52 (11), 3453-3456CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclin. species, has a clean off-target profile, and is neg. in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
- 290Hamoud, M. M. S.; Pulya, S.; Osman, N. A.; Bobde, Y.; Hassan, A. E. A.; Abdel-Fattah, H. A.; Ghosh, B.; Ghanim, A. M. Design, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitors. New J. Chem. 2020, 44, 9671– 9683, DOI: 10.1039/D0NJ01274B[Crossref], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFGlsLfF&md5=d532ffd3c380e25543df325f12bdba3aDesign, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitorsHamoud, Mohamed M. S.; Pulya, Sravani; Osman, Nermine A.; Bobde, Yamini; Hassan, Abdalla E. A.; Abdel-Fattah, Hanan A.; Ghosh, Balaram; Ghanim, Amany M.New Journal of Chemistry (2020), 44 (23), 9671-9683CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)Most of the FDA approved histone deacetylase inhibitors (HDACi) contain hydroxamate as the zinc binding group (ZBG). Hydroxamates form strong electrostatic metal chelation with divalent zinc present in HDAC. This strong zinc chelation leads to unwanted metabolic abnormalities. Therefore, the design of a non-hydroxamate moiety as a ZBG encourages medicinal chem. researchers. Here, a series of nicotinamide derivs. have been designed and synthesized as HDACi. All compds. were tested for their inhibitory activities against pan HDACs (contg. predominantly HDAC1 and HDAC2 isoenzymes) and against the HDAC3 isoform. Among these, compds. 6b and 6n showed comparable pan HDAC inhibitory activity (IC50 = 4.648 μM and IC50 = 5.481 μM, resp.) compared with BG45 (IC50 = 5.506 μM). Compd. 6b exhibited the best potency against HDAC3 with IC50 = 0.694 μM. In addn., the anti-proliferative activity of the synthesized compds. 6a-s was evaluated against three different cancer cell lines including B16F10, MCF-7, and A549. Compd. 6b(I) displayed the highest anti-proliferative potency (IC50 = 4.66 μM in B16F10 cell lines) and compds. 6b, 6c, 6h, 6i, 6l, 6m, and 6n exhibited higher cytotoxicity against all cell lines compared with the ref. BG45. The selected potent compds. also displayed significant selectivity against cancer cell lines over normal human embryonic kidney (HEK-293) cell lines. The mol. modeling study displayed possible interactions between the most potent inhibitor 6b and HDAC3 active sites. Furthermore, the predicted in silico studies of all target compds. revealed acceptable physicochem. properties and pharmacokinetic parameters.
- 291Wang, C.; Henkes, L. M.; Doughty, L. B.; He, M.; Wang, D.; Meyer-Almes, F. J.; Cheng, Y. Q. Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J. Nat. Prod. 2011, 74, 2031– 2038, DOI: 10.1021/np200324x[ACS Full Text], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFSlu7g%253D&md5=1fc01e68dd5021a37931ed1c297f8570Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative ActivitiesWang, Cheng; Henkes, Leonhard M.; Doughty, Leah B.; He, Min; Wang, Di-Fei; Meyer-Almes, Franz-Josef; Cheng, Yi-QiangJournal of Natural Products (2011), 74 (10), 2031-2038CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compd., SAHA (vorinostat, Zolinza), and one natural product, FK228 (depsipeptide, romidepsin, Istodax), approved by FDA for clin. use. The authors' studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A and thailandepsin B. HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GIC50 for over 90% of the tested cell lines at low nanomolar concns. and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.
- 292Li, X.; Tu, Z.; Li, H.; Liu, C.; Li, Z.; Sun, Q.; Yao, Y.; Liu, J.; Jiang, S. Biological evaluation of new largazole analogues: alteration of macrocyclic scaffold with click chemistry. ACS Med. Chem. Lett. 2013, 4, 132– 136, DOI: 10.1021/ml300371t[ACS Full Text], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhsl2mu7zF&md5=58d90326cc3eafe8d68e99d6a2801b8cBiological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with Click chemistryLi, Xianlin; Tu, Zhenchao; Li, Hua; Liu, Chunping; Li, Zheng; Sun, Qiao; Yao, Yiwu; Liu, Jinsong; Jiang, ShengACS Medicinal Chemistry Letters (2013), 4 (1), 132-136CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design, synthesis, and biol. evaluation of a new series of largazole analogs in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, resp. Compd. (I) bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole mol. scaffold.
- 293Taori, K.; Paul, V. J.; Luesch, H. Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J. Am. Chem. Soc. 2008, 130, 1806– 1807, DOI: 10.1021/ja7110064[ACS Full Text], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFGhtw%253D%253D&md5=bcd18bbee431e273c1b646f3c9c1388bStructure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.Taori, Kanchan; Paul, Valerie J.; Luesch, HendrikJournal of the American Chemical Society (2008), 130 (6), 1806-1807CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel cytotoxic cyclodepsipeptide, termed largazole, has been isolated from the marine cyanobacterium Symploca sp. collected in the Florida Keys. Its planar structure was elucidated by 1D and 2D NMR spectroscopy in conjunction with mass spectrometry. The abs. configuration of largazole was detd. by chem. degrdn. followed by chiral HPLC anal. Largazole possesses densely assembled unusual structural features, including a rare 4-methylthiazoline linearly fused to a thiazole in its cyclic core and a hitherto undescribed 3-hydroxy-7-mercaptohept-4-enoic acid unit incorporated in an ester, thioester, and amide framework. Largazole exhibits potent antiproliferative activity and preferentially targets cancer cells over nontransformed cells.
- 294Bowers, A.; West, N.; Taunton, J.; Schreiber, S. L.; Bradner, J. E.; Williams, R. M. Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. J. Am. Chem. Soc. 2008, 130, 11219– 11222, DOI: 10.1021/ja8033763[ACS Full Text], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXos12ru78%253D&md5=0063841a5d6a996484cdb329ff6baa64Total synthesis and biological mode of action of largazole: A potent Class I histone deacetylase inhibitorBowers, Albert; West, Nathan; Taunton, Jack; Schreiber, Stuart L.; Bradner, James E.; Williams, Robert M.Journal of the American Chemical Society (2008), 130 (33), 11219-11222CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficient total synthesis of the recently described natural substance largazole and its active metabolite largazole thiol is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-rug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite largazole thiol, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and largazole thiol have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.
- 295Ying, Y.; Taori, K.; Kim, H.; Hong, J.; Luesch, H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. J. Am. Chem. Soc. 2008, 130, 8455– 8459, DOI: 10.1021/ja8013727[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsVeksr4%253D&md5=d580c55dfc1c921346a8d79b2b96baa3Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase InhibitorYing, Yongcheng; Taori, Kanchan; Kim, Hyoungsu; Hong, Jiyong; Luesch, HendrikJournal of the American Chemical Society (2008), 130 (26), 8455-8459CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the prepn. of a series of key analogs, and the mol. target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biol. evaluation of largazole and its key analogs, including an acetyl analog, a thiol analog, and a hydroxyl analog, suggested that histone deacetylases (HDACs) are mol. targets of largazole and largazole is a class I HDAC inhibitor. In addn., structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.
- 296Seiser, T.; Kamena, F.; Cramer, N. Synthesis and biological activity of largazole and derivatives. Angew. Chem., Int. Ed. 2008, 47, 6483– 6485, DOI: 10.1002/anie.200802043[Crossref], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCksbrN&md5=e92870aac334b2051b87cf75e67efffeSynthesis and biological activity of largazole and derivativesSeiser, Tobias; Kamena, Faustin; Cramer, NicolaiAngewandte Chemie, International Edition (2008), 47 (34), 6483-6485CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A modular synthesis of the marine natural product largazole and related synthetic analogs is described. Largazole was prepd. in 10% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity.
- 297Ghosh, A. K.; Kulkarni, S. Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase. Org. Lett. 2008, 10, 3907– 3909, DOI: 10.1021/ol8014623[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVGjtbk%253D&md5=5e471389e15c2f0e207727bb9e9038a2Enantioselective Total Synthesis of (+)-Largazole, a Potent Inhibitor of Histone DeacetylaseGhosh, Arun K.; Kulkarni, SarangOrganic Letters (2008), 10 (17), 3907-3909CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (I) is described. It is a potent histone deacetylase inhibitor. The synthesis is convergent and involves the coupling of the free carboxylic acid, derived from thiazole ester II, with Boc-amino ester III, followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymic kinetic resoln. of a β-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.
- 298Nasveschuk, C. G.; Ungermannova, D.; Liu, X.; Phillips, A. J. A concise total synthesis of largazole, solution structure, and some preliminary structure activity relationships. Org. Lett. 2008, 10, 3595– 3598, DOI: 10.1021/ol8013478[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotlOmurs%253D&md5=404766f9f4fce793550504328f11f43cA Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity RelationshipsNasveschuk, Christopher G.; Ungermannova, Dana; Liu, Xuedong; Phillips, Andrew J.Organic Letters (2008), 10 (16), 3595-3598CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)A total synthesis of largazole (I) that proceeds in 8 steps from com. materials is reported, along with some structure-activity relationships. A combination of NMR studies and mol. modeling have also provided a preliminary picture of the conformation of largazole.
- 299Terracciano, S.; Di Micco, S.; Bifulco, G.; Gallinari, P.; Riccio, R.; Bruno, I. Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222. Bioorg. Med. Chem. 2010, 18, 3252– 3260, DOI: 10.1016/j.bmc.2010.03.022[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsFCkurY%253D&md5=fb504ea753abff24d7d9e825f881988eSynthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222Terracciano, Stefania; Di Micco, Simone; Bifulco, Giuseppe; Gallinari, Paola; Riccio, Raffaele; Bruno, InesBioorganic & Medicinal Chemistry (2010), 18 (9), 3252-3260CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)In the course of their ongoing efforts to discover new and more effective HDAC inhibitors for the development of anticancer agents, the authors have recently undertaken a mol. modeling study on a small collection of FR235222 analogs, synthesized in the frame of a structure-activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calcns., provided new structural insights useful for a further refinement of the tetrapeptide scaffold, which should assure an optimal interaction between the synthetic ligands and the biol. target. Using computer-based modeling methods, the authors synthesized six new cyclotetrapeptide analogs (3-8) of FR235222, bearing a carboxylic or an hydroxamic acid functionality as Zn binding moiety. Herein, the authors describe the synthesis and inhibition activity of cyclotetrapeptides on different HDAC isoforms.
- 300Zhang, Y.; Yang, P.; Chou, C. J.; Liu, C.; Wang, X.; Xu, W. Development of N-Hydroxycinnamamide-based histone deacetylase inhibitors with indole-containing cap group. ACS Med. Chem. Lett. 2013, 4, 235– 238, DOI: 10.1021/ml300366t[ACS Full Text], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkt12hsQ%253D%253D&md5=36a817a03f74290769cb0dcbbb7c5ce0Development of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap GroupZhang, Yingjie; Yang, Penghui; Chou, C. James; Liu, Chunxi; Wang, Xuejian; Xu, WenfangACS Medicinal Chemistry Letters (2013), 4 (2), 235-238CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compds. exhibited comparable, even superior, total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compd. I with moderate HDACs inhibition was progressed to isoform selectivity profile, Western blot anal., and in vivo antitumor assay. Although HDACs isoform selectivity of I was similar to that of SAHA, the Western blot results indicated that intracellular effects of I at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time, while the effect on histone H4 acetylation of I was maintained and even increased. Most importantly, compd. I exhibited promising in vivo antitumor activity in a U937 xenograft model.
- 301Zhang, L.; Zhang, Y.; Chou, C. J.; Inks, E. S.; Wang, X.; Li, X.; Hou, J.; Xu, W. Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities. ChemMedChem 2014, 9, 638– 648, DOI: 10.1002/cmdc.201300297[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGntbnM&md5=a9575d05eeef6ea997a0b435176779ddHistone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor ActivitiesZhang, Lei; Zhang, Yingjie; Chou, C. James; Inks, Elizabeth S.; Wang, Xuejian; Li, Xiaoguang; Hou, Jinning; Xu, WenfangChemMedChem (2014), 9 (3), 638-648CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of small mols. I (R = 4-ClC6H4CO, 1-naphthylsulfonyl, 2-MeOC6H4NHCO, etc.) was designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compds. was discovered. Moreover, the tested compds. have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results showed that representative compds. can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, I (R = 5-dimethylamino-1-naphthylsulfonyl) showed better performance than SAHA in blocking U937 tumor growth. Western blot anal. revealed that representative mols. can block the function of both class I HDACs and HDAC6. More importantly, the western blot results revealed that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by these compds. in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.
- 302Abdelkarim, H.; Neelarapu, R.; Madriaga, A.; Vaidya, A. S.; Kastrati, I.; Karumudi, B.; Wang, Y. T.; Taha, T. Y.; Thatcher, G. R. J.; Frasor, J.; Petukhov, P. A. Design, synthesis, molecular modeling, and biological evaluation of novel amine-based histone deacetylase inhibitors. ChemMedChem 2017, 12, 2030– 2043, DOI: 10.1002/cmdc.201700449[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvV2nsbvL&md5=fcb3babf90d0048e4806e7faaf3e674cDesign, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase InhibitorsAbdelkarim, Hazem; Neelarapu, Raghupathi; Madriaga, Antonett; Vaidya, Aditya S.; Kastrati, Irida; Karumudi, Bhargava; Wang, Yue-ting; Taha, Taha Y.; Thatcher, Gregory R. J.; Frasor, Jonna; Petukhov, Pavel A.ChemMedChem (2017), 12 (24), 2030-2043CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biol. evaluation in cellular models of cancer, and preliminary drug metab. and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-aminoheptanohydroxamic acid-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. The secondary amines were found to be generally more potent than the corresponding tertiary amines. Docking studies suggested that the SBGs of tertiary amines cannot be favorably accommodated at the gorge region of the binding site. The secondary amines with naphthalen-2-ylmethyl, 5-phenylthiophen-2-ylmethyl, and 1H-indol-2-ylmethyl (2 j) substituents exhibited the highest potency against class I HDACs: HDAC1 IC50 39-61 nm, HDAC2 IC50 260-690 nm, HDAC3 IC50 25-68 nm, and HDAC8 IC50 320-620 nm. The cytotoxicity of a representative set of secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors against HT-29, SH-SY5Y, and MCF-7 cancer cells correlated with their inhibition of HDAC1, 2, and 3 and was found to be similar to or better than that of suberoylanilide hydroxamic acid (SAHA). Compds. in this series increased the acetylation of histones H3 and H4 in a time-dependent manner. DMPK studies indicated that secondary amine 2 j is metabolically stable and has plasma and brain concns. >23- and >1.6-fold higher than the IC50 value for class I HDACs, resp. Overall, the secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors exhibit excellent lead- and drug-like properties and therapeutic capacity for cancer applications.
- 303Taha, T. Y.; Aboukhatwa, S. M.; Knopp, R. C.; Ikegaki, N.; Abdelkarim, H.; Neerasa, J.; Lu, Y.; Neelarapu, R.; Hanigan, T. W.; Thatcher, G. R. J.; Petukhov, P. A. Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based histone deacetylase 8 selective inhibitors. ACS Med. Chem. Lett. 2017, 8, 824– 829, DOI: 10.1021/acsmedchemlett.7b00126[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cls7bJ&md5=5799a2ed9d2c772db5bc4355a102f814Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective InhibitorsTaha, Taha Y.; Aboukhatwa, Shaimaa M.; Knopp, Rachel C.; Ikegaki, Naohiko; Abdelkarim, Hazem; Neerasa, Jayaprakash; Lu, Yunlong; Neelarapu, Raghupathi; Hanigan, Thomas W.; Thatcher, Gregory R. J.; Petukhov, Pavel A.ACS Medicinal Chemistry Letters (2017), 8 (8), 824-829CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biol. evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based I and II exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, resp. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of I and II was evaluated in neuroblastoma cell lines, and II displayed concn.-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of I and II was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.
- 304Chou, C. J.; Herman, D.; Gottesfeld, J. M. Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J. Biol. Chem. 2008, 283, 35402– 35409, DOI: 10.1074/jbc.M807045200[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVylsr3L&md5=ffcdd2b6a6884d7fa48076c9bf228011Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone DeacetylasesChou, C. James; Herman, David; Gottesfeld, Joel M.Journal of Biological Chemistry (2008), 283 (51), 35402-35409CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clin. development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compds. have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC50 values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 Is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with Ki of ∼14 nM, 15 times lower than the Ki for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides vs. hydroxamates as gene activators.
- 305Yao, Y.; Tu, Z.; Liao, C.; Wang, Z.; Li, S.; Yao, H.; Li, Z.; Jiang, S. Discovery of novel class i histone deacetylase inhibitors with promising in vitro and in vivo antitumor activities. J. Med. Chem. 2015, 58, 7672– 7680, DOI: 10.1021/acs.jmedchem.5b01044[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCgurnI&md5=3069fbc43dc2cc5ead040bad2021cae3Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor ActivitiesYao, Yiwu; Tu, Zhengchao; Liao, Chenzhong; Wang, Zhen; Li, Shang; Yao, Hequan; Li, Zheng; Jiang, ShengJournal of Medicinal Chemistry (2015), 58 (19), 7672-7680CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compd. I [R = H] an IC50 of 2.78 nM for binding to the HDAC1 protein, and the prodrugs I [R = Me(CH2)6C(O)] and I [R = MeC(O)] also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compds. I [R = Me(CH2)6C(O)] and I [R = MeC(O)] show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addn., compd. I [R = MeC(O)] exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no obsd. toxicity. Thus, prodrug I [R = MeC(O)] has therapeutic potential as a new class of anticancer agent for further clin. translation.
- 306Soumyanarayanan, U.; Ramanujulu, P. M.; Mustafa, N.; Haider, S.; Fang Nee, A. H.; Tong, J. X.; Tan, K. S. W.; Chng, W. J.; Dymock, B. W. Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor. Eur. J. Med. Chem. 2019, 184, 111755, DOI: 10.1016/j.ejmech.2019.111755[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2gs7fP&md5=bb0b3d40a7ea91b92d9f12dccd922851Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitorSoumyanarayanan, Uttara; Ramanujulu, Pondy Murugappan; Mustafa, Nurulhuda; Haider, Shozeb; Fang Nee, Adina Huey; Tong, Jie Xin; Tan, Kevin S. W.; Chng, Wee Joo; Dymock, Brian W.European Journal of Medicinal Chemistry (2019), 184 (), 111755CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed addnl. low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast cancer and four hematol. cancer cell lines was supported by pharmacodynamic studies on a preferred mol., 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modeling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compd. potency, explaining the obsd. HDAC3/6 selectivity. A subset of the compds. also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favorable DMPK profile warranting further investigation of the therapeutic potential of these compds.
- 307Adhikari, N.; Amin, S. A.; Trivedi, P.; Jha, T.; Ghosh, B. HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches. Eur. J. Med. Chem. 2018, 157, 1127– 1142, DOI: 10.1016/j.ejmech.2018.08.081[Crossref], [PubMed], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1emtrzO&md5=2e916b713c3d7442ea082d0688ec3da0HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approachesAdhikari, Nilanjan; Amin, Sk. Abdul; Trivedi, Prakruti; Jha, Tarun; Ghosh, BalaramEuropean Journal of Medicinal Chemistry (2018), 157 (), 1127-1142CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compds. comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that mol. size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these mols. possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.
- 308Amin, S. A.; Adhikari, N.; Jha, T.; Ghosh, B. Designing potential HDAC3 inhibitors to improve memory and learning. J. Biomol. Struct. Dyn. 2019, 37, 2133– 2142, DOI: 10.1080/07391102.2018.1477625[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWru7rK&md5=35290ed8294866346db72077fdbde266Designing potential HDAC3 inhibitors to improve memory and learningAmin, Sk. Abdul; Adhikari, Nilanjan; Jha, Tarun; Ghosh, BalaramJournal of Biomolecular Structure and Dynamics (2019), 37 (8), 2133-2142CODEN: JBSDD6; ISSN:0739-1102. (Taylor & Francis Ltd.)The work presented here explores the structural and physicochem. features important for benzamide-based HDAC3 inhibitors to get an idea about the design aspect of potential inhibitors. A no. of mol. modeling studies (3D-QSAR CoMFA and CoMSIA, Bayesian classification modeling) were performed on 113 diverse set of benzamide-based HDAC3 inhibitors. All these models developed are statistically reliable and correlate the SAR observations. Electron withdrawing substitution is favorable but the bulky hydrophobic group at the cap region reduces HDAC3 inhibition. Hydrophobicity and steric feature of the aryl linker function favor the activity. Aryl group substituted benzamide functionality is not favorable for HDAC3 inhibition. The amide function of the benzamide moiety is essential for Zn2+ chelation and the carboxylic acid function may serve as a hydrogen bond acceptor (HBA) feature. Moreover, electron withdrawing substituent at the benzamide moiety influences activity whereas steric and hydrophobic substituents reduce HDAC3 inhibition. Overall, this study may provide a valuable insight on the design of better active HDAC3 inhibitors in future.
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Abstract
Figure 1
Figure 1. Lysine deacetylation of histone proteins catalyzed by HDAC.
Figure 2
Figure 2. Different classes of HDACs.
Figure 3
Figure 3. HDAC inhibitors in modulating diverse biological conditions.
Figure 4
Figure 4. Approved and clinically evaluated HDAC inhibitors.(76−107)
Figure 5
Figure 5. (A) Structure of HDAC3 (PDB 4A69) [A chain, indigo; B chain, yellow; C chain, red; D chain, green; zinc ions are shown as magenta spheres; [Ins(1,4,5,6)P4] is located in the interface of A, B and C chains shown as scaled ball and stick model]. (B) Intermolecular interactions of zinc, acetate and surrounding amino acids at A chain. (C) Intermolecular interactions of zinc, acetate, and surrounding amino acids at B chain.
Figure 6
Figure 6. Potential HDAC inhibitors used to evaluate the binding pattern and orientation with several HDACs
Figure 7
Figure 7. Structures of docked TSA (4, green), SK-683 (19, purple), and CG-1521 (20, cyan) in the active sites of HDAC1 (a), HDAC2 (b), HDAC3 (c), and HDAC8 (d) (left) and their top views in these proteins with surface representations (right). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.
Figure 8
Figure 8. Structures of docked SAHA (1, blue), MS-275 (15, red), and NVP-LAQ824 (21, yellow) in the active sites of HDAC1 (a), HDAC3 (b), and HDAC8 (c). Reprinted with permission from ref (132). Copyright 2005 American Chemical Society.
Figure 9
Figure 9. Role of HDAC3 in various disease conditions.
Figure 10
Figure 10. Role of HDAC3 in estrogen-dependent cyclin D1 expression.
Figure 11
Figure 11. HDAC3 inhibition by RGFP966 (22) modulates the disruption of HDAC3/STAT3/PD-L1 pathway.
Figure 12
Figure 12. Role of HDAC3 to form VM networks in glioma. Adapted with permission from ref (181). Copyright 2015 John Wiley and Sons.
Figure 13
Figure 13. Inhibition of HDAC3 by BG45 (24) modulates the caspase-3 and PARP-mediated apoptotic pathway.
Figure 14
Figure 14. Role of HDAC3 in arthritis.
Figure 15
Figure 15. Hydroxamates as potent and HDAC3-selective inhibitors.
Figure 16
Figure 16. Indole-based hydroxamates as potent and HDAC3-selective inhibitors.
Figure 17
Figure 17. Some benzamide-based HDAC3-selective inhibitors.
Figure 18
Figure 18. Molecular docking interaction of compound 50 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.
Figure 19
Figure 19. Benzamide-based, potent, and HDAC3-selective inhibitors.
Figure 20
Figure 20. (A) Ferrocene-based benzamides as potential HDAC3 inhibitors. (B) Molecular docking interaction of compounds 63 and 64 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow. (C) 2-Aminobenzamides as effective HDAC3 inhibitors. (D) Effective HDAC3-selective proteolysis targeting chimera (PROTAC) containing benzamide as ZBG.
Figure 21
Figure 21. Arylhydrazides as potent and HDAC3-selective inhibitors.
Figure 22
Figure 22. Indole cap containing hydrazides as potent and HDAC3-selective inhibitors.
Figure 23
Figure 23. Molecular docking interaction of compound 77 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line. Hydrogen bonding interactions are shown in dotted green arrow.
Figure 24
Figure 24. Panobinostat-based hydrazides as potent and HDAC3-selective inhibitors.
Figure 25
Figure 25. Modified benzamide derivatives as potent and highly HDAC3-selective inhibitors.
Figure 26
Figure 26. Ethylketones and nicotinamides as effective HDAC3 inhibitors.
Figure 27
Figure 27. Molecular docking interaction of compound 101 with HDAC3 (PDB 4A69). Coordination with Zn2+ ion is shown in dotted orange line; hydrogen bonding interactions are shown in dotted green arrow; π–π stacking interactions are shown in dotted blue line.
Figure 28
Figure 28. Thailandepsin analogs and natural products as potent and HDAC3-selective inhibitors.
Figure 29
Figure 29. (A) Hydroxamate-based dual HDAC1/3 inhibitors. (B) Benzamide-based dual HDAC1/3 inhibitors. (C) Hydrazide-based dual HDAC1/3 inhibitors. (D) Romidepsin-based dual HDAC1/3 selective inhibitors. (E) Dual HDAC3/6 selective inhibitors.
References
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- 1Adhikari, N.; Amin, S. A.; Jha, T. Selective and nonselective HDAC8 inhibitors: A therapeutic patent review. Pharm. Pat. Anal. 2018, 7, 259– 276, DOI: 10.4155/ppa-2018-0019[Crossref], [PubMed], [CAS], Google Scholar1https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXitFGgs7s%253D&md5=203ad904b2ba51380c1ccd8f2181e486Selective and nonselective HDAC8 inhibitors: a therapeutic patent reviewAdhikari, Nilanjan; Abdul Amin, Sk; Jha, TarunPharmaceutical Patent Analyst (2018), 7 (6), 259-276CODEN: PPAHCN; ISSN:2046-8954. (Future Science Ltd.)A review. Histone deacetylase 8 (HDAC8) is one of the attractive therapeutic anticancer targets. HDAC8 has been overexpressed in a variety of human cancers. Therefore, HDAC8 inhibitors offer beneficial effects in the treatment of solid and hematol. tumors. Different HDAC inhibitors entered into different phases of clin. studies. However, selectivity towards specific HDAC8 enzyme is still demanding. In this patent review, a no. of patented selective and nonselective HDAC8 inhibitors along with their implication as anticancer agents have been discussed in details. Mols. should possess modified fish-like structural arrangement to impart potency and selectivity towards HDAC8. This comprehensive patent anal. will surely provide newer aspects of designing selective HDAC8 inhibitors targeted to anticancer therapy in future.
- 2Biswas, S.; Rao, C. M. Epigenetics in cancer: fundamentals and beyond. Pharmacol. Ther. 2017, 173, 118– 134, DOI: 10.1016/j.pharmthera.2017.02.011[Crossref], [PubMed], [CAS], Google Scholar2https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXislOru7o%253D&md5=1173d02b0cc70a467944d59d2d2a35fcEpigenetics in cancer: Fundamentals and BeyondBiswas, Subhankar; Rao, C. MallikarjunaPharmacology & Therapeutics (2017), 173 (), 118-134CODEN: PHTHDT; ISSN:0163-7258. (Elsevier)Activation of oncogenes or the deactivation of tumor suppressor genes has long been established as the fundamental mechanism leading towards carcinogenesis. Although this age old axiom is vastly accurate, thorough study over the last 15 years has given us unprecedented information on the involvement of epigenetic in cancer. Various biochem. pathways that are essential towards tumorigenesis are regulated by the epigenetic phenomenons like remodeling of nucleosome by histone modifications, DNA methylation and miRNA mediated targeting of various genes. Moreover the presence of mutations in the genes controlling the epigenetic players has further strengthened the assocn. of epigenetics in cancer. This merger has opened up newer avenues for targeted anti-cancer drug therapy with numerous pharmaceutical industries focusing on expanding their research and development pipeline with epigenetic drugs. The information provided here elaborates the elementary phenomena of the various epigenetic regulators and discusses their alteration assocd. with the development of cancer. We also highlight the recent developments in epigenetic drugs combining preclin. and clin. data to signify this evolving field in cancer research.
- 3Amin, S. A.; Adhikari, N.; Kotagiri, S.; Jha, T.; Ghosh, B. Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamides. Eur. J. Med. Chem. 2019, 166, 369– 380, DOI: 10.1016/j.ejmech.2019.01.077[Crossref], [PubMed], [CAS], Google Scholar3https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXivFygtLo%253D&md5=f4ca2691087eb3ee67a53e1feda65568Histone deacetylase 3 inhibitors in learning and memory processes with special emphasis on benzamidesAmin, Sk. Abdul; Adhikari, Nilanjan; Kotagiri, Sonali; Jha, Tarun; Ghosh, BalaramEuropean Journal of Medicinal Chemistry (2019), 166 (), 369-380CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Among numerous essential processes, memory and learning are important work of the brain. Epigenetic manipulations through histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been implicated in memory function by modulating memory storage-related gene expression. Among these HDACs, HDAC3 is found to be important in the long-term memory process. Histone deacetylase inhibitors (HDACIs) have been established to have direct involvement to enhance the memory function through upregulation of hippocampal NR2B mRNA and phosphorylation of cAMP -response element binding (CREB) at the NR2B gene. Though HDACIs were initially implicated as potent anticancer agents, these are also found to enhance memory or ameliorate deficits in memory dysfunction. It is done through inducing a histone hyperacetylated state. HDAC3 is a neg. regulator of memory and learning and thus, deletion of HDAC3 in the dorsal hippocampus may lead to an enhanced long-term memory. Therefore, identification of potential and selective HDAC3 inhibitors may be useful in ameliorating long-term memory function and learning. In this review, detail chemico-biol. and structural information of HDAC3 in memory and learning functions and benzamide-based HDAC3 inhibitors has been focussed. This may help to achieve a deep insight so that potent and selective benzamide-based HDAC3 inhibitors may be designed in future to combat memory and learning-related dysfunctions.
- 4Amin, S. A.; Adhikari, N.; Ghosh, B.; Jha, T. Histone Deacetylase 3 and Its inhibitors. In Advances in Medicine and Biology; Berhardt, L. V., Ed.; Nova Science Publishers: New York, 2019; Vol. 145, Chapter 4, pp 131– 202.
- 5Sarkar, R.; Banerjee, S.; Amin, S. A.; Adhikari, N.; Jha, T. Histone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A review. Eur. J. Med. Chem. 2020, 192, 112171, DOI: 10.1016/j.ejmech.2020.112171[Crossref], [PubMed], [CAS], Google Scholar5https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXkvVeisr0%253D&md5=d9911556755793d92c3e073b89b9b00eHistone deacetylase 3 (HDAC3) inhibitors as anticancer agents: A reviewSarkar, Rajat; Banerjee, Suvankar; Amin, Sk Abdul; Adhikari, Nilanjan; Jha, TarunEuropean Journal of Medicinal Chemistry (2020), 192 (), 112171CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Among different Histone deacetylases (HDACs), histone deacetylase 3 (HDAC3) is an epigenetic drug target which is currently marked as a potential therapeutic strategy to combat various cancers. HDAC3 inhibitors are effective for the treatment of cancers, different neurodegenerative disorders, diabetes mellitus, cardiac diseases, HIV, inflammatory diseases, rheumatoid arthritis (RA), etc. Inhibition of HDAC3 metalloenzyme is a dynamic approach for drug design and discovery. This approach has gained considerable interest in recent years. The development of an effective therapeutic agent against HDAC3 is still challenging. A lot of work is still in demand. This current communication is a part of our extended work on HDAC3 inhibitors to achieve deep insight of knowledge about the structural information of HDAC3 inhibitors. This article is unique in terms of detailed structure-activity relationships (SARs) anal. This may help to find out some important clues to design better active HDAC3 inhibitors in the future.
- 6Banerjee, S.; Adhikari, N.; Amin, S. A.; Jha, T. Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overview. Eur. J. Med. Chem. 2019, 164, 214– 240, DOI: 10.1016/j.ejmech.2018.12.039[Crossref], [PubMed], [CAS], Google Scholar6https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXltF2q&md5=cf4ca3ae21d10662da0ce32f0c336b72Histone deacetylase 8 (HDAC8) and its inhibitors with selectivity to other isoforms: An overviewBanerjee, Suvankar; Adhikari, Nilanjan; Amin, Sk Abdul; Jha, TarunEuropean Journal of Medicinal Chemistry (2019), 164 (), 214-240CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. The histone deacetylases (HDACs) enzymes provided crucial role in transcriptional regulation of cells through deacetylation of nuclear histone proteins. The pan-HDAC inhibitors can confront these conditions but have chances to affect epigenetic functions of other HDAC isoforms. Designing of selective HDAC8 inhibitors is a key feature to combat the pathophysiol. and diseased conditions involving the HDAC8 activity. This review is concerned about the structural and positional aspects of HDAC8 in the HDAC family. It also covers the contributions of HDAC8 in the pathophysiol. conditions, a preliminary discussion about the recent scenario of HDAC8 inhibitors. This review might help to deliver the structural, functional and computational information in order to identify and design potent and selective HDAC8 inhibitors for target specific treatment of diseases involving HDAC8 enzymic activity.
- 7Chakrabarti, A.; Oehme, I.; Witt, O.; Oliveira, G.; Sippl, W.; Romier, C.; Pierce, R. J.; Jung, M. HDAC8: A multifaceted target for therapeutic interventions. Trends Pharmacol. Sci. 2015, 36, 481– 492, DOI: 10.1016/j.tips.2015.04.013[Crossref], [PubMed], [CAS], Google Scholar7https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXotlGqsL4%253D&md5=c99b5c390930dc17398d15f20127758bHDAC8: a multifaceted target for therapeutic interventionsChakrabarti, Alokta; Oehme, Ina; Witt, Olaf; Oliveira, Guilherme; Sippl, Wolfgang; Romier, Christophe; Pierce, Raymond J.; Jung, ManfredTrends in Pharmacological Sciences (2015), 36 (7), 481-492CODEN: TPHSDY; ISSN:0165-6147. (Elsevier Ltd.)Histone deacetylase 8 (HDAC8) is a class I histone deacetylase implicated as a therapeutic target in various diseases, including cancer, X-linked intellectual disability, and parasitic infections. It is a structurally well-characterized enzyme that also deacetylates nonhistone proteins. In cancer, HDAC8 is a major 'epigenetic player' that is linked to deregulated expression or interaction with transcription factors crit. to tumorigenesis. In the parasite Schistosoma mansoni and in viral infections, HDAC8 is a novel target to subdue infection. The current challenge remains in the development of potent selective inhibitors that would specifically target HDAC8 with fewer adverse effects compared with pan-HDAC inhibitors. Here, we review HDAC8 as a drug target and discuss inhibitors with respect to their structural features and therapeutic interventions.
- 8Amin, S. A.; Adhikari, N.; Jha, T. Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discovery. Future Med. Chem. 2017, 9, 2211– 2237, DOI: 10.4155/fmc-2017-0130[Crossref], [PubMed], [CAS], Google Scholar8https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1M3ls1eitg%253D%253D&md5=f0dced85072243a221ab3d666576f424Structure-activity relationships of hydroxamate-based histone deacetylase-8 inhibitors: reality behind anticancer drug discoveryAmin Sk Abdul; Adhikari Nilanjan; Jha TarunFuture medicinal chemistry (2017), 9 (18), 2211-2237 ISSN:.The pan-histone deacetylase (HDAC) inhibitors comprise a fish-like structural orientation where hydrophobic aryl- and zinc-binding groups act as head and tail, respectively of a fish. The linker moiety correlates the body of the fish linking head and tail groups. Despite these pan-HDAC inhibitors, selective HDAC-8 inhibitors are still in demand as a safe remedy. HDAC-8 is involved in invasion and metastasis in cancer. This review deals with the rationale behind HDAC-8 inhibitory activity and selectivity along with detailed structure-activity relationships of diverse hydroxamate-based HDAC-8 inhibitors. HDAC-8 inhibitory potency may be increased by modifying the fish-like pharmacophoric features of such type of pan-HDAC inhibitors. This review may provide a preliminary basis to design and optimize new lead molecules with higher HDAC-8 inhibitory activity. This work may surely enlighten in providing useful information in the field of target-specific anticancer therapy.
- 9Gregoretti, I. V.; Lee, Y. M.; Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 2004, 338, 17– 31, DOI: 10.1016/j.jmb.2004.02.006[Crossref], [PubMed], [CAS], Google Scholar9https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXisFyksro%253D&md5=1748e3b88d8f3b774db50eb19799f63cMolecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic AnalysisGregoretti, Ivan V.; Lee, Yun-Mi; Goodson, Holly V.Journal of Molecular Biology (2004), 338 (1), 17-31CODEN: JMOBAK; ISSN:0022-2836. (Elsevier)Histone deacetylases (HDACs) modify core histones and participate in large regulatory complexes that both suppress and enhance transcription. Recent studies indicate that some HDACs can act on non-histone proteins as well. Interest in these enzymes is growing because HDAC inhibitors appear to be promising therapeutic agents against cancer and a variety of other diseases. Thus far, 11 members of the HDAC family have been identified in humans, but few have been characterized in detail. To better define the biol. function of these proteins, make maximal use of studies performed in other systems, and assist in drug development efforts, we have performed a phylogenetic anal. of all HDAC-related proteins in all fully sequenced free-living organisms. Previous analyses have divided non-sirtuin HDACs into two groups, classes 1 and 2. We find that HDACs can be divided into three equally distinct groups: class 1, class 2, and a third class consisting of proteins related to the recently identified human HDAC11 gene. We term this novel group "class 4" to distinguish it from the unrelated "class 3" sirtuin deacetylases. Anal. of gene duplication events indicates that the common ancestor of metazoan organisms contained two class 1, two class 2, and a single class 4 HDAC. Examn. of HDAC characteristics in light of these evolutionary relationships leads to functional predictions, among them that self-assocn. is common among HDAC proteins. All three HDAC classes (including class 4) exist in eubacteria. Phylogenetic anal. of bacterial HDAC relatives suggests that all three HDAC classes precede the evolution of histone proteins and raises the possibility that the primary activity of some "histone deacetylase" enzymes is directed against non-histone substrates.
- 10Fu, W.; Wu, K.; Duan, J. Sequence and expression analysis of histone deacetylases in rice. Biochem. Biophys. Res. Commun. 2007, 356, 843– 850, DOI: 10.1016/j.bbrc.2007.03.010[Crossref], [PubMed], [CAS], Google Scholar10https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXjvFOmsbY%253D&md5=38a512409528357bd76945a28b96db3bSequence and expression analysis of histone deacetylases in riceFu, Wenqun; Wu, Keqiang; Duan, JunBiochemical and Biophysical Research Communications (2007), 356 (4), 843-850CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)Histone acetylation levels are detd. by the action of histone acetyltransferases and histone deacetylases (HDACs). Sequence similarity and profile searching tools were used to analyze the genome sequence of rice (Oryzae sativa) for genes encoding HDAC proteins. The rice RPD3/HDA1-family HDAC proteins can be divided into four classes based on sequence similarity and phylogenetic anal. of sequences obtained from the rice genome. The spatial expression pattern of rice HDACs genes indicated that some HDAC genes have different expression profiles. Furthermore, our anal. indicated that expression of HDA705, HDT701, and HDT702 could be affected by salicylic acid, jasmonic acid or abscisic acid. Expression of HDA714, SRT702, and SRT701 could be modulated by abiotic stresses, such as cold, mannitol and salt. These results indicate that different HDAC genes have distinct expression patterns and members of rice HDAC families may be involved in plant response to environmental stresses.
- 11Mano, T.; Suzuki, T.; Tsuji, S.; Iwata, A. Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregates. PLoS One 2014, 9, e111277 DOI: 10.1371/journal.pone.0111277[Crossref], [PubMed], [CAS], Google Scholar11https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitFOksLfN&md5=7340313f14bf09977cbec1d5374fdbe5Differential effect of HDAC3 on cytoplasmic and nuclear huntingtin aggregatesMano, Tatsuo; Suzuki, Takayoshi; Tsuji, Shoji; Iwata, AtsushiPLoS One (2014), 9 (11), e111277/1-e111277/9, 9 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Histone deacetylases (HDACs) are potential therapeutic targets of polyglutamine (pQ) diseases including Huntington's disease (HD) that may function to correct aberrant transcriptional deactivation caused by mutant pQ proteins. HDAC3 is a unique class 1 HDAC found in both the cytoplasm and in the nucleus. However, the precise functions of HDAC3 in the two cellular compartments are only vaguely known. HDAC3 directly binds to huntingtin (Htt) with short pQ and this interaction is important for suppressing neurotoxicity induced by HDAC3. With long pQ Htt, the interaction with HDAC3 is inhibited, and this supposedly promotes neuronal death, indicating that HDAC3 would be a good therapeutic target for HD. However, the knockout of one HDAC3 allele did not show any efficacy in reducing neurodegenerative symptoms in a mouse model of HD. Therefore, the role of HDAC3 in the pathogenesis of HD has yet to be fully elucidated. We attempted to resolve this issue by focusing on the different roles of HDAC3 on cytoplasmic and nuclear Htt aggregates. In addn. to supporting the previous findings, we found that HDAC3 preferentially binds to nuclear Htt over cytoplasmic ones. Specific HDAC3 inhibitors increased the total amt. of Htt aggregates by increasing the amt. of nuclear aggregates. Both cytoplasmic and nuclear Htt aggregates were able to suppress endogenous HDAC3 activity, which led to decreased nuclear proteasome activity. Therefore, we concluded that Htt aggregates impair nuclear proteasome activity through the inhibition of HDAC3. Our findings provide new insights regarding cross-compartment proteasome regulation.
- 12Verdin, E.; Dequiedt, F.; Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 2003, 19, 286– 293, DOI: 10.1016/S0168-9525(03)00073-8[Crossref], [PubMed], [CAS], Google Scholar12https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXjtFeqt7o%253D&md5=0d9eca937cd5bd87e1f0640ab6223de4Class II histone deacetylases: versatile regulatorsVerdin, Eric; Dequiedt, Franck; Kasler, Herbert G.Trends in Genetics (2003), 19 (5), 286-293CODEN: TRGEE2; ISSN:0168-9525. (Elsevier Science Ltd.)A review. Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in eukaryotes. Histone deacetylases (HDACs) catalyze the deacetylation of Lys residues in the histone N-terminal tails and are found in large multiprotein complexes with transcriptional co-repressors. Human HDACs are grouped into 3 classes based on their similarity to known yeast factors: class I HDACs are similar to yeast transcriptional repressor yRPD3, class II HDACs to yHDA1, and class III HDACs to ySIR2. Here, the focus is on the biol. of class II HDACs. These newly discovered enzymes have been implicated as global regulators of gene expression during cell differentiation and development. The authors discuss their emerging biol. functions and the mol. mechanisms by which they are regulated.
- 13Lahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.; Jones, P.; Neddermann, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.; De Francesco, R.; Steinkühler, C.; Gallinari, P. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 17335– 17340, DOI: 10.1073/pnas.0706487104[Crossref], [PubMed], [CAS], Google Scholar13https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXht1ymtrjO&md5=a8345ac68fbddc344e9e0737472e2863Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylasesLahm, A.; Paolini, C.; Pallaoro, M.; Nardi, M. C.; Jones, P.; Neddermann, P.; Sambucini, S.; Bottomley, M. J.; Lo Surdo, P.; Carfi, A.; Koch, U.; De Francesco, R.; Steinkuehler, C.; Gallinari, P.Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (44), 17335-17340CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on std. substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymic assay, suggesting that the obsd. activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on std. substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nε2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this "gain of function phenotype" could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro. Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
- 14Zhang, Y.; Li, N.; Caron, C.; Matthias, G.; Hess, D.; Khochbin, S.; Matthias, P. HDAC-6 interacts with and deacetylates tubulin and microtubules in vivo. EMBO J. 2003, 22, 1168– 1179, DOI: 10.1093/emboj/cdg115[Crossref], [PubMed], [CAS], Google Scholar14https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXit1yls7c%253D&md5=0d2b6dd552163866b85f14471ac600f7HDAC-6 interacts with and deacetylates tubulin and microtubules in vivoZhang, Yu; Li, Na; Caron, Cecile; Matthias, Gabriele; Hess, Daniel; Khochbin, Saadi; Matthias, PatrickEMBO Journal (2003), 22 (5), 1168-1179CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Microtubules are cylindrical cytoskeletal structures found in almost all eukaryotic cell types which are involved in a great variety of cellular processes. Reversible acetylation on the ε-amino group of α-tubulin Lys40 marks stabilized microtubule structures and may contribute to regulating microtubule dynamics. Yet, the enzymes catalyzing this acetylation/deacetylation have remained unidentified until recently. Here we report that β-tubulin interacts with histone deacetylase-6 (HDAC-6) in a yeast two-hybrid assay and in vitro. We find that HDAC-6 is a micro tubule-assocd. protein capable of deacetylating α-tubulin in vivo and in vitro. HDAC-6's microtubule binding and deacetylation functions both depend on the hdac domains. Overexpression of HDAC-6 in mammalian cells leads to tubulin hypoacetylation. In contrast, inhibition of HDAC-6 function by two independent mechanisms-pharmacol. (HDAC inhibitors) or genetic (targeted inactivation of HDAC-6 in embryonic stem cells)-leads to hyperacetylation of tubulin and microtubules. Taken together, our data provide evidence that HDAC-6 might act as a dual deacetylase for tubulin and histones, and suggest the possibility that acetylated non-histone proteins might represent novel targets for pharmacol. therapy by HDAC inhibitors.
- 15Gao, L.; Cueto, M. A.; Asselbergs, F.; Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 2002, 277, 25748– 25755, DOI: 10.1074/jbc.M111871200[Crossref], [PubMed], [CAS], Google Scholar15https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XlsVWht7g%253D&md5=9d22c3b434691e5bce5e13db8b500eddCloning and functional characterization of HDAC11, a novel member of the human histone deacetylase familyGao, Lin; Cueto, Maria A.; Asselbergs, Fred; Atadja, PeterJournal of Biological Chemistry (2002), 277 (28), 25748-25755CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The authors have cloned and characterized a human cDNA that belongs to the histone deacetylase family, which the authors designate as HDAC11. The predicted HDAC11 amino acid sequence reveals an open reading frame of 347 residues with a corresponding mol. mass of 39 kDa. Sequence analyses of the putative HDAC11 protein indicate that it contains conserved residues in the catalytic core regions shared by both class I and II mammalian HDAC enzymes. Putative orthologs of HDAC11 exist in primate, mouse, Drosophila, and plant. Epitope-tagged HDAC11 protein expressed in mammalian cells displays histone deacetylase activity in vitro. Furthermore, HDAC11's enzymic activity is inhibited by trapoxin, a known histone deacetylase inhibitor. Multiple tissue Northern blot and real-time PCR expts. show that the high expression level of HDAC11 transcripts is limited to kidney, heart, brain, skeletal muscle, and testis. Epitope-tagged HDAC11 protein localizes predominantly to the cell nucleus. Co-immunopptn. expts. indicate that HDAC11 may be present in protein complexes that also contain HDAC6. These results indicate that HDAC11 is a novel and unique member of the histone deacetylase family and it may have distinct physiol. roles from those of the known HDACs.
- 16Mrakovcic, M.; Kleinheinz, J.; Fröhlich, L. F. p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell death. Int. J. Mol. Sci. 2019, 20, 2415, DOI: 10.3390/ijms20102415[Crossref], [CAS], Google Scholar16https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXosVGmsg%253D%253D&md5=d74b939314d54d581024c3ef97664733In p53 at the crossroads between different types of HDAC inhibitor-mediated cancer cell deathMrakovcic, Maria; Kleinheinz, Johannes; Froehlich, Leopold F.International Journal of Molecular Sciences (2019), 20 (10), 2415/1-2415/32CODEN: IJMCFK; ISSN:1422-0067. (MDPI AG)A review. Cancer is a complex genetic and epigenetic-based disease that has developed an armada of mechanisms to escape cell death. The deregulation of apoptosis and autophagy, which are basic processes essential for normal cellular activity, are commonly encountered during the development of human tumors. In order to assist the cancer cell in defeating the imbalance between cell growth and cell death, histone deacetylase inhibitors (HDACi) have been employed to reverse epigenetically deregulated gene expression caused by aberrant post-translational protein modifications. These interfere with histone acetyltransferase- and deacetylase-mediated acetylation of both histone and non-histone proteins, and thereby exert a wide array of HDACi-stimulated cytotoxic effects. Key determinants of HDACi lethality that interfere with cellular growth in a multitude of tumor cells are apoptosis and autophagy, which are either mutually exclusive or activated in combination. Here, we compile known mol. signals and pathways involved in the HDACi-triggered induction of apoptosis and autophagy. Currently, the factors that det. the mode of HDACi-elicited cell death are mostly unclear. Correspondingly, we also summarized as yet established intertwined mechanisms, in particular with respect to the oncogenic tumor suppressor protein p53, that drive the interplay between apoptosis and autophagy in response to HDACi. In this context, we also note the significance to det. the presence of functional p53 protein levels in the cancer cell. The confirmation of the context-dependent function of autophagy will pave the way to improve the benefit from HDACi-mediated cancer treatment.
- 17Manal, M.; Chandrasekar, M. J.; Gomathi Priya, J.; Nanjan, M. J. Inhibitors of histone deacetylase as antitumor agents: A critical review. Bioorg. Chem. 2016, 67, 18– 42, DOI: 10.1016/j.bioorg.2016.05.005[Crossref], [PubMed], [CAS], Google Scholar17https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xoslaltbc%253D&md5=82e5562d9b74dfef2d6077bbceccd505Inhibitors of histone deacetylase as antitumor agents: A critical reviewManal, Mohammed; Chandrasekar, M. J. N.; Gomathi Priya, Jeyapal; Nanjan, M. J.Bioorganic Chemistry (2016), 67 (), 18-42CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)A review. Histone deacetylase (E.C. 3.5.1.98 - HDAC) is an amidohydrolase involved in deacetylating the histone lysine residues for chromatin remodeling and thus plays a vital role in the epigenetic regulation of gene expression. Due to its aberrant activity and over expression in several forms of cancer, HDAC is considered as a potential anticancer drug target. HDAC inhibitors alter the acetylation status of histone and nonhistone proteins to regulate various cellular events such as cell survival, differentiation and apoptosis in tumor cells and thus exhibit anticancer activity. Till date, four drugs, namely Vorinostat (SAHA), Romidepsin (FK-228), Belinostat (PXD-101) and Panobinostat (LBH-589) have been granted FDA approval for cancer and several HDAC inhibitors are currently in various phases of clin. trials, either as monotherapy and/or in combination with existing/novel anticancer agents. Regardless of this, today scientific efforts have fortified the quest for newer and novel HDAC inhibitors that show isoform selectivity. This review focuses on the chem. of the mols. of two classes of HDAC inhibitors, namely short chain fatty acids and hydroxamic acids, investigated so far as novel therapeutic agents for cancer.
- 18Xu, W. S.; Parmigiani, R. B.; Marks, P. A. Histone deacetylase inhibitors: Molecular mechanisms of action. Oncogene 2007, 26, 5541– 5552, DOI: 10.1038/sj.onc.1210620[Crossref], [PubMed], [CAS], Google Scholar18https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXovFersrY%253D&md5=227a7c5d26028e99d412441596ba02aeHistone deacetylase inhibitors: molecular mechanisms of actionXu, W. S.; Parmigiani, R. B.; Marks, P. A.Oncogene (2007), 26 (37), 5541-5552CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. This review focuses on the mechanisms of action of histone deacetylase (HDAC) inhibitors (HDACi), a group of recently discovered targeted' anticancer agents. There are 18 HDACs, which are generally divided into four classes, based on sequence homol. to yeast counterparts. Classical HDACi such as the hydroxamic acid-based vorinostat (also known as SAHA and Zolinza) inhibits classes I, II and IV, but not the NAD+-dependent class III enzymes. In clin. trials, vorinostat has activity against hematol. and solid cancers at doses well tolerated by patients. In addn. to histones, HDACs have many other protein substrates involved in regulation of gene expression, cell proliferation and cell death. Inhibition of HDACs causes accumulation of acetylated forms of these proteins, altering their function. Thus, HDACs are more properly called 'lysine deacetylases.'. HDACi induces different phenotypes in various transformed cells, including growth arrest, activation of the extrinsic and/or intrinsic apoptotic pathways, autophagic cell death, reactive oxygen species (ROS)-induced cell death, mitotic cell death and senescence. In comparison, normal cells are relatively more resistant to HDACi-induced cell death. The plurality of mechanisms of HDACi-induced cell death reflects both the multiple substrates of HDACs and the heterogeneous patterns of mol. alterations present in different cancer cells.
- 19Richon, V. M.; Sandhoff, T. W.; Rifkind, R. A.; Marks, P. A. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 10014– 10019, DOI: 10.1073/pnas.180316197[Crossref], [PubMed], [CAS], Google Scholar19https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXmtlehsL4%253D&md5=7ada3abdf0a2109b73efa2770d5db6cbHistone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylationRichon, Victoria M.; Sandhoff, Todd W.; Rifkind, Richard A.; Marks, Paul A.Proceedings of the National Academy of Sciences of the United States of America (2000), 97 (18), 10014-10019CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylases (HDACs) catalyze the removal of acetyl groups on the amino-terminal lysine residues of core nucleosomal histones. This activity is assocd. generally with transcriptional repression. We have reported previously that inhibition of HDAC activity by hydroxamic acid-based hybrid polar compds., such as suberoylanilide hydroxamic acid (SAHA), induces differentiation and/or apoptosis of transformed cells in vitro and inhibits tumor growth in vivo. SAHA is a potentially new therapeutic approach to cancer treatment and is in Phase I clin. trials. In several tumor cell lines examd., HDAC inhibitors alter the expression of less than 1% of expressed genes, including the cell cycle kinase inhibitor p21WAF1. In T24 bladder carcinoma cells, SAHA induces up to a 9-fold increase in p21WAF1 mRNA and protein, which is, at least in part, because of an increase in the rate of transcription of the gene. SAHA causes an accumulation of acetylated histones H3 and H4 in total cellular chromatin by 2 h, which is maintained through 24 h of culture. An increase in the accumulation of acetylated H3 and H4 was detected throughout the p21WAF1 promoter and the structural gene after culture with SAHA. The level of histone acetylation did not change in chromatin assocd. with the actin and p27 genes, and their mRNA expression was not altered during culture of T24 cells with SAHA. Thus, the present findings indicate that the induction of p21WAF1 by SAHA is regulated, at least in part, by the degree of acetylation of the gene-assocd. histones and that this induced increase in acetylation is gene selective.
- 20Nawrocki, S. T.; Carew, J. S.; Douglas, L.; Cleveland, J. L.; Humphreys, R.; Houghton, J. A. Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21 Cip1-dependent decrease in survivin levels. Cancer Res. 2007, 67, 6987– 6994, DOI: 10.1158/0008-5472.CAN-07-0812[Crossref], [PubMed], [CAS], Google Scholar20https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnslOitL8%253D&md5=9409f3e41a5ddfa903b76d2a6dfa8123Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin LevelsNawrocki, Steffan T.; Carew, Jennifer S.; Douglas, Leslie; Cleveland, John L.; Humphreys, Robin; Houghton, Janet A.Cancer Research (2007), 67 (14), 6987-6994CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was crit. for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21+/+ cells but not in the HCT116 p21-/- cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
- 21Wang, H.; Zhou, W.; Zheng, Z.; Zhang, P.; Tu, B.; He, Q.; Zhu, W. G. The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair 2012, 11, 146– 156, DOI: 10.1016/j.dnarep.2011.10.014[Crossref], [PubMed], [CAS], Google Scholar21https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XotVCksw%253D%253D&md5=eefbeedd5c1475560e83c20359b45cc9The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damageWang, Haiying; Zhou, Wen; Zheng, Zhixing; Zhang, Ping; Tu, Bo; He, Qihua; Zhu, Wei-GuoDNA Repair (2012), 11 (2), 146-156CODEN: DRNEAR; ISSN:1568-7864. (Elsevier B.V.)Histone deacetylase (HDAC) inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin. As a potent HDAC inhibitor, depsipeptide not only modulates histone deacetylation but also activates non-histone protein p53 to inhibit cancer cell growth. However, the mechanism of depsipeptide-induced p53 transactivity remains unknown. Here, we show that depsipeptide causes DNA damage through induction of reactive oxygen species (ROS) generation, as demonstrated by a comet assay and by detection of the phosphorylation of H2AX. Depsipeptide induced oxidative stress was confirmed to relate to a disturbance in redn.-oxidn. (redox) reactions through inhibition of the transactivation of thioredoxin reductase (TrxR) in human cancer cells. Upon treatment with depsipeptide, p53 phosphorylation at threonine 18 (Thr18) was specifically induced. Furthermore, we also demonstrated that phosphorylation of p53 at Thr18 is required for p53 acetylation at lysine 373/382 and for p21 expression in response to depsipeptide treatment. Our results demonstrate that depsipeptide plays an anti-neoplastic role by generating ROS to elicit p53/p21 pathway activation.
- 22Schrump, D. S. Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin. Cancer Res. 2009, 15, 3947– 3957, DOI: 10.1158/1078-0432.CCR-08-2787[Crossref], [PubMed], [CAS], Google Scholar22https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXntlOis74%253D&md5=5c00e794043ab54dc9116537b31afb9cCytotoxicity Mediated by Histone Deacetylase Inhibitors in Cancer Cells: Mechanisms and Potential Clinical ImplicationsSchrump, David S.Clinical Cancer Research (2009), 15 (12), 3947-3957CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)A review. Aberrant expression of epigenetic regulators of gene expression contributes to initiation and progression of cancer. During recent years, considerable research efforts have focused on the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in cancer cells, and the identification of pharmacol. agents that modulate gene expression via inhibition of HDACs. The following review highlights recent studies pertaining to HDAC expression in cancer cells, the plieotropic mechanisms by which HDAC inhibitors (HDACi) mediate antitumor activity, and the potential clin. implications of HDAC inhibition as a strategy for cancer therapy.
- 23Li, H.; Wu, X. Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cells. Biochem. Biophys. Res. Commun. 2004, 324, 860– 867, DOI: 10.1016/j.bbrc.2004.09.130[Crossref], [PubMed], [CAS], Google Scholar23https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2cXotlCmtrk%253D&md5=085568cab56226e68e0cb41dcb87bea0Histone deacetylase inhibitor, Trichostatin A, activates p21WAF1/CIP1 expression through downregulation of c-myc and release of the repression of c-myc from the promoter in human cervical cancer cellsLi, Hui; Wu, XinxingBiochemical and Biophysical Research Communications (2004), 324 (2), 860-867CODEN: BBRCA9; ISSN:0006-291X. (Elsevier)Histone deacetylase (HDAC) inhibitors have shown promise in clin. cancer therapy and to consistently induce p21WAF1/CIP1 expression in a p53-independent manner and via increased acetylation of the chromatin at the Sp1 sites in the p21WAF1/CIP1 promoter region. However, the exact mechanism by which HDAC inhibitors induce p21WAF1/CIP1 remains unclear. In this study, we obsd. that Trichostatin A (TSA), a HDAC inhibitor, induced strikingly p21WAF1/CIP1 expression in human cervical cancer (HeLa) cells, and this induction correlated with downregulation of c-myc expression. Coincident with this observation, knock down of c-myc with a c-myc specific small interfering RNA dramatically induced expression of p21WAF1/CIP1 in these cancer cells. These data suggest that c-myc may play a crit. role in repression of p21WAF1/CIP1 expression in HeLa cells. More importantly, using chromatin immunopptn. assay, we obsd. for the first time that c-myc bound to the endogenous p21WAF1/CIP1 promoter in untreated HeLa cells, but not in TSA-treated cells. Taken together, TSA induced c-myc downregulation and release from the endogenous p21WAF1/CIP1 promoter contributes, at least partially, to transcriptional activation of the p21WAF1/CIP1 in HeLa cells.
- 24Robbins, A. R.; Jablonski, S. A.; Yen, T. J.; Yoda, K.; Robey, R.; Bates, S. E.; Sackett, D. L. Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle 2005, 4, 717– 726, DOI: 10.4161/cc.4.5.1690[Crossref], [PubMed], [CAS], Google Scholar24https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XitVOnsrY%253D&md5=f6190ef862d5b673c3858a9e59316257Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatinRobbins, April R.; Jablonski, Sandra A.; Yen, Tim J.; Yoda, Kinya; Robey, Rob; Bates, Susan E.; Sackett, Dan L.Cell Cycle (2005), 4 (5), 717-726CODEN: CCEYAS; ISSN:1538-4101. (Landes Bioscience)The kinetochore, a multi-protein complex assembled on centromeric chromatin in mitosis, is essential for sister chromosome segregation. We show here that inhibition of histone deacetylation blocks mitotic progression at prometaphase in two human tumor cell lines by interfering with kinetochore assembly. Decreased amts. of hBUB1, CENP-F and the motor protein CENP-E were present on kinetochores of treated cells. These kinetochores failed to nucleate and inefficiently captured microtubules, resulting in activation of the mitotic checkpoint. Addn. of histone deacetylase inhibitors prior to the end of S-phase resulted in decreased HP1-β on pericentromeric heterochromatin in S-phase and G2, decreased pericentromeric targeting of Aurora B kinase, resulting in decreased premitotic phosphorylation of pericentromeric histone H3(S10) in G2, followed by assembly of deficient kinetochores in M-phase. HP1-β, Aurora B and the affected kinetochore proteins all were present at normal levels in treated cells; thus, effects of the inhibitors on mitotic progression do not seem to reflect changes in gene expression. In vitro kinase activity of Aurora B isolated from treated cells was unaffected. We propose that the increased presence in pericentromeric heterochromatin of histone H3 acetylated at K9 is responsible for the mitotic defects resulting from inhibition of histone deacetylation.
- 25Magnaghi-Jaulin, L.; Eot-Houllier, G.; Fulcrand, G.; Jaulin, C. Histone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpoint. Cancer Res. 2007, 67, 6360– 6367, DOI: 10.1158/0008-5472.CAN-06-3012[Crossref], [PubMed], [CAS], Google Scholar25https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnsVyqtLs%253D&md5=b5cabbd79fdcd6cfb404175541cbb3aeHistone deacetylase inhibitors induce premature sister chromatid separation and override the mitotic spindle assembly checkpointMagnaghi-Jaulin, Laura; Eot-Houllier, Gregory; Fulcrand, Geraldine; Jaulin, ChristianCancer Research (2007), 67 (13), 6360-6367CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Histone deacetylase inhibitors (HDACI) are /powerful antiproliferative drugs, and are currently undergoing clin. trials as antitumor agents. It would be valuable for both cancer therapy and our knowledge of basic cellular processes to understand the mechanisms by which HDACIs block cell proliferation. Most current models postulate that HDACIs allow the reexpression of tumor suppressor genes silenced in cancer cells. However, other mechanisms, distinct from transcription regulation, may participate in HDACI antiproliferative properties. We report that HDACI treatment induces premature sister chromatid sepn. in cells in which the mitotic spindle assembly checkpoint (SAC) has already been activated. This effect was transcription-independent. In addn., HDACI-treated mitotic cells displayed SAC inactivation characteristics, including anaphase-promoting complex/cyclosome target degrdn., cyclin-dependent kinase 1 inactivation, histone H3 dephosphorylation, and loss of the SAC component MAD2 from the kinetochore. Thus, HDAC inhibition renders the SAC ineffective. Our findings help elucidate the mol. mechanisms of proliferative cell death induced by HDACI treatment and may allow new HDACI-based preclin. and clin. trial protocols to be redesigned so as to target mitosis.
- 26Dowling, M.; Voong, K. R.; Kim, M.; Keutmann, M. K.; Harris, E.; Kao, G. D. Mitotic spindle checkpoint inactivation by trichostatin a defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents. Cancer Biol. Ther. 2005, 4, 205, DOI: 10.4161/cbt.4.2.1441
- 27Liu, L. T.; Chang, H. C.; Chiang, L. C.; Hung, W. C. Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion. Cancer Res. 2003, 63, 3069– 3072[PubMed], [CAS], Google Scholar27https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1eitLk%253D&md5=92b3c13b7eaa1f61d53f5345e2f1f7daHistone Deacetylase Inhibitor Up-Regulates RECK to Inhibit MMP-2 Activation and Cancer Cell InvasionLiu, Li-Teh; Chang, Hui-Chiu; Chiang, Lien-Chai; Hung, Wen-ChunCancer Research (2003), 63 (12), 3069-3072CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Histone deacetylase (HDAC) inhibitors are known to exert antimetastatic and antiangiogenic activity in vitro and in vivo. RECK is a membrane-anchored glycoprotein that neg. regulates matrix metalloproteinases (MMPs) and inhibits tumor metastasis and angiogenesis. In this study, we test the possibility that HDAC inhibitor may increase RECK expression to inhibit MMP activation and cancer cell invasion. Our results showed that trichostatin A (TSA) up-regulated RECK via transcriptional activation in CL-1 human lung cancer cells. Flow cytometric anal. demonstrated that RECK protein on cell surface was increased after treatment of TSA. Moreover, up-regulation of RECK expression by TSA attenuated MMP-2 activity. To explore whether HDAC inhibitor-induced inhibition of MMP-2 activation is indeed mediated via RECK, we used small interference RNA (siRNA) to block RECK expression and found that inhibition of RECK by siRNA abolished the inhibitory effect of TSA on MMP-2 activation. In addn., TSA suppressed the invasive ability of CL-1 cells. Taken together, this study reveals a novel mechanism by which HDAC inhibitors suppress tumor invasion and provides a new strategy for cancer therapy.
- 28Estella, C.; Herrer, I.; Atkinson, S. P.; Quiñonero, A.; Martínez, S.; Pellicer, A.; Simon, C. Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion. PLoS One 2012, 7, e30508 DOI: 10.1371/journal.pone.0030508[Crossref], [PubMed], [CAS], Google Scholar28https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XitlaqsLo%253D&md5=63831500a8b1697799d6597b4bd40a0aInhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasionEstella, Carlos; Herrer, Isabel; Atkinson, Stuart P.; Quinonero, Alicia; Martinez, Sebastian; Pellicer, Antonio; Simon, CarlosPLoS One (2012), 7 (1), e30508CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Invasion of the trophoblast into the maternal decidua is regulated by both the trophectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins, and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpack condensed chromatin activating gene expression. In this study, we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3; decreased MMP-2, MMP-9 and uPA and had an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated cells. In addn., in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is assocd. with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.
- 29Tran, A. D. A.; Marmo, T. P.; Salam, A. A.; Che, S.; Finkelstein, E.; Kabarriti, R.; Xenias, H. S.; Mazitschek, R.; Hubbert, C.; Kawaguchi, Y.; Sheetz, M. P.; Yao, T. P.; Bulinski, J. C. HDAC6 deacetylation of tubulin modulates dynamics of cellular adhesions. J. Cell Sci. 2007, 120, 1469– 1479, DOI: 10.1242/jcs.03431[Crossref], [PubMed], [CAS], Google Scholar29https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXlsFSjtbs%253D&md5=6e25ead47afba657cf58bf4287df25fbHDAC6 deacetylation of tubulin modulates dynamics of cellular adhesionsTran, Andy Dong-Anh; Marmo, Timothy P.; Salam, Ambar A.; Che, Sally; Finkelstein, Erik; Kabarriti, Rafi; Xenias, Harry S.; Mazitschek, Ralph; Hubbert, Charlotte; Kawaguchi, Yoshiharu; Sheetz, Michael P.; Yao, Tso-Pang; Bulinski, J. ChloeJournal of Cell Science (2007), 120 (8), 1469-1479CODEN: JNCSAI; ISSN:0021-9533. (Company of Biologists Ltd.)Genetic or pharmacol. alteration of the activity of histone deacetylase 6 (HDAC6) induces a parallel alteration in cell migration. Using tubacin to block deacetylation of α-tubulin, and not other HDAC6 substrates, yielded a motility redn. equiv. to agents that block all NAD-independent HDACs. Accordingly, the authors investigated how the failure to deacetylate tubulin contributes to decreased motility in HDAC6-inhibited cells. Testing the hypothesis that motility is reduced because cellular adhesion is altered, it was found that inhibiting HDAC6 activity toward tubulin rapidly increased the total adhesion area. Next, the authors investigated the mechanism of the adhesion area increase. Formation of adhesions proceeded normally and cell spreading was more rapid in the absence of active HDAC6; however, photobleaching assays and adhesion breakdown showed that adhesion turnover was slower. To test the role of hyperacetylated tubulin in altering adhesion turnover, the authors measured microtubule dynamics in HDAC6-inhibited cells because dynamic microtubules are required to target adhesions for turnover. HDAC6 inhibition yielded a decrease in microtubule dynamics that was sufficient to decrease focal adhesion turnover. Thus, the results suggest a scenario in which the decreased dynamics of hyperacetylated microtubules in HDAC6-inhibited cells compromises their capacity to mediate the focal adhesion dynamics required for rapid cell migration.
- 30Terui, T.; Murakami, K.; Takimoto, R.; Takahashi, M.; Takada, K.; Murakami, T.; Minami, S.; Matsunaga, T.; Takayama, T.; Kato, J.; Niitsu, Y. Induction of PIG3 and NOXA through acetylation of p53 at 320 and 373 lysine residues as a mechanism for apoptotic cell death by histone deacetylase inhibitors. Cancer Res. 2003, 63, 8948– 8954[PubMed], [CAS], Google Scholar30https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVSqtbnM&md5=32a8a2d566f752ac86b10c469ee11e5eInduction of PIG3 and NOXA through Acetylation of p53 at 320 and 373 Lysine Residues as a Mechanism for Apoptotic Cell Death by Histone Deacetylase InhibitorsTerui, Takeshi; Murakami, Ken; Takimoto, Rishu; Takahashi, Minoru; Takada, Koichi; Murakami, Tsuzuku; Minami, Shinya; Matsunaga, Takuya; Takayama, Tetsuji; Kato, Junji; Niitsu, YoshiroCancer Research (2003), 63 (24), 8948-8954CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)Two controversial issues regarding p53 are whether it is involved in apoptosis induction of tumor cells by a histone deacetylase (HDAC) inhibitor and, given that p53 is indeed involved, which genes of acetylated p53 targets are responsible for giving rise to apoptotic death. We, in the present study, first confirmed that some substantial extent of apoptotic cell death was seen when p53-deficient cells (KATO-III) were transfected with wild-type p53 and treated with sodium butyrate (SB) or trichostatin A. By Western blotting, using specific antibodies, we then demonstrated that residues 320, 373, and 382 lysines of p53 were acetylated in KATO-III cells transfected with wild-type p53 (KATO-III/p53) treated with a HDAC inhibitor. However, as revealed by terminal deoxynucleotidyl transferase-mediated nick end labeling staining, only those KATO-III cells transfected with K320R p53 or K373R p53 became insensitive to the HDAC inhibitor, suggesting that these two residues of p53 may be essential for HDAC inhibitor-induced apoptosis, whereas others such as K382R p53 may not. Furthermore, reverse transcription-PCR demonstrated that among various p53-related proapoptotic genes, expression of PIG3 and NOXA were clearly enhanced by SB treatment in KATO-III/p53 cells but not in KATO-III/K320R or KATO-III/K373R cells. Finally, we revealed that apoptosis could be evoked by SB even in cells where p53 mutations occur at residues other than 320 lysine or 373 lysine (TMK-1 and HSC-39 cells) and that this apoptosis was significantly, although not totally, suppressed by the anti-p53 antisense. It was, therefore, concluded that acetylation of the p53 mol. at residues 320 and 373, giving rise to up-regulation of PIG3 and NOXA, is one of the mechanisms for induction of apoptosis by HDAC inhibitors in cancer cells.
- 31Inoue, S.; Riley, J.; Gant, T. W.; Dyer, M. J.; Cohen, G. M. Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by bim and noxa. Leukemia 2007, 21, 1773– 1782, DOI: 10.1038/sj.leu.2404760[Crossref], [PubMed], [CAS], Google Scholar31https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnvVeltbk%253D&md5=722720f03d80c397ac194e922033ae6fApoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and NoxaInoue, S.; Riley, J.; Gant, T. W.; Dyer, M. J. S.; Cohen, G. M.Leukemia (2007), 21 (8), 1773-1782CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Several histone deacetylase inhibitors (HDACi), which have recently entered early clin. trials, exert their anticancer activity in part through the induction of apoptosis although the precise mechanism of this induction is not known. Induction of apoptosis by structurally diverse HDACi in primary cells from patients with chronic lymphocytic leukemia (CLL) and different leukemic cell lines was mediated by the Bcl-2 regulated intrinsic pathway and demonstrated a requirement for de novo protein synthesis. A marked time-dependent induction of the pro-apoptotic BH3-only proteins, Bim, Noxa and Bmf was obsd., which preceded the induction of apoptosis. A key role for both Bim and Noxa was proposed in HDACi-mediated apoptosis based on our findings that siRNA for Bim and Noxa but not Bmf largely prevented the HDACi-induced loss in mitochondrial membrane potential, caspase processing and phosphatidylserine externalization. Noxa, induced by HDACi, in CLL cells and tumor cell lines, bound extensively to Mcl-1, a major anti-apoptotic Bcl-2 family member present in CLL cells. Our data strongly suggests that HDACi induce apoptosis primarily through inactivation of anti-apoptotic Bcl-2 family members by increases in Bim and Noxa and highlights these increases as a potential clin. target for CLL/lymphoma therapy.
- 32Zhang, X. D.; Gillespie, S. K.; Borrow, J. M.; Hersey, P. The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Biochem. Pharmacol. 2003, 66, 1537– 1545, DOI: 10.1016/S0006-2952(03)00509-4[Crossref], [PubMed], [CAS], Google Scholar32https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnvVeqs7s%253D&md5=095588ae46c4ab5fe4f39e583b658955The histone deacetylase inhibitor suberic bishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosisZhang, Xu Dong; Gillespie, Susan K.; Borrow, Jodie M.; Hersey, PeterBiochemical Pharmacology (2003), 66 (8), 1537-1545CODEN: BCPCA6; ISSN:0006-2952. (Elsevier Science B.V.)A review. TRAIL appears to be a promising anticancer agent in that it induces apoptosis in a wide range of cancer cells but not normal tissues. Sensitivity of melanoma cells to TRAIL-induced apoptosis varied considerably because of their development of various resistance mechanisms against apoptosis. We discuss in this report the potential effect of a histone deacetylase inhibitor SBHA on TRAIL-induced apoptosis. Histone deacetylase (HDAC) inhibitors regulate histone acetylation and thereby modulate the transcriptional activity of certain genes leading to cell growth arrest, cellular differentiation, and apoptosis. Suberic bishydroxamate (SBHA) is a relatively new HDAC inhibitor that induced apoptosis in the majority of melanoma cell lines through a mitochondrial and caspase-dependent pathway. This was due to its regulation of the expression of multiple proteins that are involved in either the mitochondrial apoptotic pathway (Bcl-2 family members) or the final phase of apoptosis (caspase-3 and XIAP). Co-treatment with SBHA at nontoxic doses and TRAIL resulted in a marked increase in TRAIL-induced apoptosis of melanoma, but showed no toxicity to melanocytes. SBHA appeared to sensitize melanoma to TRAIL-induced apoptosis by up-regulation of pro-apoptotic proteins in the TRAIL-induced apoptotic pathway such as caspase-8, caspase-3, Bid, Bak, and Bax, and up-regulation of the BH3 domain only protein, Bim. This, together with activated Bid, may have acted synergistically to cause changes in mitochondria. Treatment with SBHA also resulted in down-regulation of antiapoptotic members of the Bcl-2 family, Bcl-XL and Mcl-1, and the IAP member, XIAP. These changes would further facilitate apoptotic signaling. SBHA appeared therefore to be a potent agent in overcoming resistance of melanoma to TRAIL-induced apoptosis.
- 33Bolden, J. E.; Shi, W.; Jankowski, K.; Kan, C. Y.; Cluse, L.; Martin, B. P.; MacKenzie, K. L.; Smyth, G. K.; Johnstone, R. W. HDAC inhibitors induce tumor-cell selective pro-apoptotic transcriptional responses. Cell Death Dis. 2013, 4, e519 DOI: 10.1038/cddis.2013.9[Crossref], [PubMed], [CAS], Google Scholar33https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVyksbbJ&md5=68ece9fa3ee1f2a3e7e4ef75229da5deHDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responsesBolden, J. E.; Shi, W.; Jankowski, K.; Kan, C.-Y.; Cluse, L.; Martin, B. P.; MacKenzie, K. L.; Smyth, G. K.; Johnstone, R. W.Cell Death & Disease (2013), 4 (Feb.), e519CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)The identification of recurrent somatic mutations in genes encoding epigenetic enzymes has provided a strong rationale for the development of compds. that target the epigenome for the treatment of cancer. This notion is supported by biochem. studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases to promoter regions through assocn. with oncogenic fusion proteins such as PML-RARα and AML1-ETO. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis; however, it remains unclear why tumor cells are more sensitive to HDACi-induced cell death than normal cells. Herein, we assessed the biol. and mol. responses of isogenic normal and transformed cells to the FDA-approved HDACi vorinostat and romidepsin. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time-course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontol. and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor-cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance, indicating that specific and selective engagement of the intrinsic apoptotic pathway underlies the tumor-cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells while leaving normal cells relatively unharmed is fundamental to their successful clin. application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and implicates specific mols. and pathways in the tumor-selective cytotoxic activity of these compds.
- 34Zhang, Y.; Adachi, M.; Kawamura, R.; Imai, K. Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ. 2006, 13, 129– 140, DOI: 10.1038/sj.cdd.4401686[Crossref], [PubMed], [CAS], Google Scholar34https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXht1yktbrN&md5=54bc6d7d5842e9c4649ebd3d5b7b3e4aBmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosisZhang, Y.; Adachi, M.; Kawamura, R.; Imai, K.Cell Death and Differentiation (2006), 13 (1), 129-140CODEN: CDDIEK; ISSN:1350-9047. (Nature Publishing Group)Histone deacetylase (HDAC) inhibitors modify transcription of selected genes and eventually induce apoptosis. However, mol. mechanisms for their proapoptotic activity remain unclear. We here demonstrate that HDAC inhibitors FK228 and CBHA preferentially upregulated the BH3-only protein Bmf in a broad range of cancer cells. In contrast, HDAC1 overexpression distinctly reduced Bmf expression. FK228 induced histones H3 and H4 acetylation at Bmf promoter region, but not at its 3' region, suggesting that histone hyperacetylation causes Bmf transcriptional activation. Knockdown of Bmf transcripts rescued cells from FK228 or CBHA-induced cell death, disruption of mitochondrial membrane potential (ΔΨm) and DNA fragmentation. Taken together, FK228 and CBHA activate Bmf transcription by histone hyperacetylation at its promoter region, and inhibition of this action decreased their proapoptotic activity, thereby highlighting a central role of Bmf in HDAC inhibitor-mediated apoptosis.
- 35Bolden, J. E.; Peart, M. J.; Johnstone, R. W. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discovery 2006, 5, 769– 784, DOI: 10.1038/nrd2133[Crossref], [PubMed], [CAS], Google Scholar35https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVCltrY%253D&md5=91e55ee942fda3e4e2055ddf299fc866Anticancer activities of histone deacetylase inhibitorsBolden, Jessica E.; Peart, Melissa J.; Johnstone, Ricky W.Nature Reviews Drug Discovery (2006), 5 (9), 769-784CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addn., the activity of non-histone proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes assocd. with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclin. studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the mol. events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
- 36Tang, S.; Cheng, B.; Zhe, N.; Ma, D.; Xu, J.; Li, X.; Guo, Y.; Wu, W.; Wang, J. Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway. Anti-Cancer Drugs 2018, 29, 61– 74, DOI: 10.1097/CAD.0000000000000568[Crossref], [PubMed], [CAS], Google Scholar36https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFOitbzN&md5=ea90a24c0f18f4018affc32f27a83fd4Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathwayTang, Sishi; Cheng, Bingqing; Zhe, Nana; Ma, Dan; Xu, Jibing; Li, Xinyao; Guo, Yongling; Wu, Weibing; Wang, JishiAnti-Cancer Drugs (2018), 29 (1), 61-74CODEN: ANTDEV; ISSN:0959-4973. (Lippincott Williams & Wilkins)Multiple myeloma (MM) is a hematol. malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of mol. targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138 mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, esp. the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clin. use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematol. malignancies.
- 37Al-Yacoub, N.; Fecker, L. F.; Möbs, M.; Plötz, M.; Braun, F. K.; Sterry, W.; Eberle, J. Apoptosis induction by SAHA in cutaneous T-cell lymphoma cells is related to downregulation of c-FLIP and enhanced TRAIL signaling. J. Invest. Dermatol. 2012, 132, 2263– 2274, DOI: 10.1038/jid.2012.125[Crossref], [PubMed], [CAS], Google Scholar37https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmtlGqtbk%253D&md5=585527a348f26be6561e5b9968692222Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL SignalingAl-Yacoub, Nadya; Fecker, Lothar F.; Moebs, Markus; Ploetz, Michael; Braun, Frank K.; Sterry, Wolfram; Eberle, JuergenJournal of Investigative Dermatology (2012), 132 (9), 2263-2274CODEN: JIDEAE; ISSN:0022-202X. (Nature Publishing Group)Suberoylanilide hydroxamic acid (SAHA) has been approved for the treatment of cutaneous T-cell lymphoma (CTCL), but its mode of action remained largely elusive. As shown here in four CTCL cell lines, loss of cell viability correlated with significant time- and dose-dependent induction of apoptosis, whereas cytotoxicity was less pronounced. Both extrinsic and intrinsic apoptosis pathways were activated, as seen by processing of initiator caspases 8 and 9, loss of mitochondrial membrane potential, and cytochrome c release. Characteristically, antiapoptotic mediators such as Mcl-1, XIAP, survivin, and c-FLIP were downregulated. Consistent with its crit. function, c-FLIP overexpression resulted in a significant decrease of SAHA-mediated apoptosis. Enhanced sensitivity to TRAIL (TNF-related apoptosis-inducing ligand) and enhanced TRAIL signaling was seen in CTCL cell lines with high sensitivity, whereas cell lines with moderate response were characterized by downregulation of TRAIL-R2 and weaker TRAIL expression. Comparable proapoptotic responses to SAHA and to the combination with TRAIL were seen in ex vivo tumor T cells of CTCL patients. Thus, activation of extrinsic apoptosis pathways, related to c-FLIP downregulation and enhanced TRAIL signaling, appeared as characteristic for CTCL cell responsiveness to SAHA. An improved understanding of the pathways may facilitate its targeted use and the selection of suitable combinations.
- 38Sung, E. S.; Kim, A.; Park, J. S.; Chung, J.; Kwon, M. H.; Kim, Y. S. Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells. Apoptosis 2010, 15, 1256– 1269, DOI: 10.1007/s10495-010-0521-9[Crossref], [PubMed], [CAS], Google Scholar38https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1aqtLvF&md5=653c41ac58b241f38d88850ef7e2440bHistone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cellsSung, Eun-Sil; Kim, Aeyung; Park, Joon Seong; Chung, Junho; Kwon, Myung-Hee; Kim, Yong-SungApoptosis (2010), 15 (10), 1256-1269CODEN: APOPFN; ISSN:1360-8185. (Springer)Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several anti-apoptotic proteins (c-FLIP, Bcl-2, Bcl-XL, XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a crit. step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.
- 39Shankar, S.; Singh, T. R.; Fandy, T. E.; Luetrakul, T.; Ross, D. D.; Srivastava, R. K. Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. Int. J. Mol. Med. 2005, 16, 1125– 1138, DOI: 10.3892/ijmm.16.6.1125[Crossref], [PubMed], [CAS], Google Scholar39https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtlWrt7zE&md5=2a7597bf3e9666159a8e355a7d4a5b0dInteractive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathwaysShankar, Sharmila; Singh, Thiyam R.; Fandy, Tamer E.; Luetrakul, Thitidaj; Ross, Douglas D.; Srivastava, Rakesh K.International Journal of Molecular Medicine (2005), 16 (6), 1125-1138CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.
- 40Insinga, A.; Monestiroli, S.; Ronzoni, S.; Gelmetti, V.; Marchesi, F.; Viale, A.; Altucci, L.; Nervi, C.; Minucci, S.; Pelicci, P. G. Inhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathway. Nat. Med. 2005, 11, 71– 76, DOI: 10.1038/nm1160[Crossref], [PubMed], [CAS], Google Scholar40https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2M%252FgvFeitw%253D%253D&md5=b6a5382cfb91cb583c0efee7c9e44bfcInhibitors of histone deacetylases induce tumor-selective apoptosis through activation of the death receptor pathwayInsinga Alessandra; Monestiroli Silvia; Ronzoni Simona; Gelmetti Vania; Marchesi Francesco; Viale Andrea; Altucci Lucia; Nervi Clara; Minucci Saverio; Pelicci Pier GiuseppeNature medicine (2005), 11 (1), 71-6 ISSN:1078-8956.Histone deacetylases (HDACs) regulate transcription and specific cellular functions, such as tumor suppression by p53, and are frequently altered in cancer. Inhibitors of HDACs (HDACIs) possess antitumor activity and are well tolerated, supporting the idea that their use might develop as a specific strategy for cancer treatment. The molecular basis for their selective antitumor activity is, however, unknown. We investigated the effects of HDACIs on leukemias expressing the PML-RAR or AML1-ETO oncoproteins, known to initiate leukemogenesis through deregulation of HDACs. Here we report that: (i) HDACIs induce apoptosis of leukemic blasts, although oncogene expression is not sufficient to confer HDACI sensitivity to normal cells; (ii) apoptosis is p53 independent and depends, both in vitro and in vivo, upon activation of the death receptor pathway (TRAIL and Fas signaling pathways); (iii) TRAIL, DR5, FasL and Fas are upregulated by HDACIs in the leukemic cells, but not in normal hematopoietic progenitors. These results show that sensitivity to HDACIs in leukemias is a property of the fully transformed phenotype and depends on activation of a specific death pathway.
- 41McCann, C.; Crawford, N.; Majkut, J.; Holohan, C.; Armstrong, C. W. D.; Maxwell, P. J.; Ong, C. W.; LaBonte, M. J.; McDade, S. S.; Waugh, D. J.; Longley, D. B. Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonists. Cell Death Dis. 2018, 9, 1081, DOI: 10.1038/s41419-018-1125-5[Crossref], [PubMed], [CAS], Google Scholar41https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cvitFWntQ%253D%253D&md5=b5a534af3156f34e24763b2a43253570Cytoplasmic FLIP(S) and nuclear FLIP(L) mediate resistance of castrate-resistant prostate cancer to apoptosis induced by IAP antagonistsMcCann Christopher; Crawford Nyree; Majkut Joanna; Holohan Caitriona; Armstrong Chris W D; Maxwell Pamela J; Ong Chee Wee; LaBonte Melissa J; McDade Simon S; Waugh David J; Longley Daniel BCell death & disease (2018), 9 (11), 1081 ISSN:.Expression of tumor necrosis factor-α (TNFα) in the serum of prostate cancer patients is associated with poorer outcome and progression to castrate-resistant (CRPC) disease. TNFα promotes the activity of NFκB, which regulates a number of anti-apoptotic and proinflammatory genes, including those encoding the inhibitor of apoptosis proteins (IAPs); however, in the presence of IAP antagonists, TNFα can induce cell death. In the presence of recombinant or macrophage-derived TNFα, we found that IAP antagonists triggered degradation of cIAP1 and induced formation of Complex-IIb, consisting of caspase-8, FADD and RIPK1 in CRPC models; however, no, or modest levels of apoptosis were induced. This resistance was found to be mediated by both the long (L) and short (S) splice forms of the caspase-8 inhibitor, FLIP, another NFκB-regulated protein frequently overexpressed in CRPC. By decreasing FLIP expression at the post-transcriptional level in PC3 and DU145 cells (but not VCaP), the Class-I histone deacetylase (HDAC) inhibitor Entinostat promoted IAP antagonist-induced cell death in these models in a manner dependent on RIPK1, FADD and Caspase-8. Of note, Entinostat primarily targeted the nuclear rather than cytoplasmic pool of FLIP(L). While the cytoplasmic pool of FLIP(L) was highly stable, the nuclear pool was more labile and regulated by the Class-I HDAC target Ku70, which we have previously shown regulates FLIP stability. The efficacy of IAP antagonist (TL32711) and Entinostat combination and their effects on cIAP1 and FLIP respectively were confirmed in vivo, highlighting the therapeutic potential for targeting IAPs and FLIP in proinflammatory CRPC.
- 42Robert, C.; Rassool, F. V. HDAC inhibitors: roles of DNA damage and repair. Adv. Cancer Res. 2012, 116, 87– 129, DOI: 10.1016/B978-0-12-394387-3.00003-3[Crossref], [PubMed], [CAS], Google Scholar42https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1Cgsb4%253D&md5=12be09097e3208dbf4840549ecae1efeHDAC inhibitors: roles of DNA damage and repairRobert, Carine; Rassool, Feyruz V.Advances in Cancer Research (2012), 116 (Histone Deacetylase Inhibitors as Cancer Therapeutics), 87-129CODEN: ACRSAJ; ISSN:0065-230X. (Elsevier Inc.)A review. Histone deacetylase inhibitors (HDACis) increase gene expression through induction of histone acetylation. However, it remains unclear whether specific gene expression changes det. the apoptotic response following HDACis administration. Herein, we discuss evidence that HDACis trigger in cancer and leukemia cells not only widespread histone acetylation but also actual increases in reactive oxygen species (ROS) and DNA damage that are further increased following treatment with DNA-damaging chemotherapies. While the origins of ROS prodn. are not completely understood, mechanisms, including inflammation and altered antioxidant signaling, have been reported. While the generation of ROS is an explanation, at least in part, for the source of DNA damage obsd. with HDACi treatment, DNA damage can also be independently induced by changes in the DNA repair activity and chromatin remodeling factors. Recent development of sirtuin inhibitors (SIRTis) has shown that, similar to HDACis, these drugs induce increases in ROS and DNA damage used singly, or in combination with HDACis and other drugs. Thus, induction of apoptosis by HDACis/SIRTis may result through oxidative stress and DNA damage mechanisms in addn. to direct activation of apoptosis-inducing genes. Nevertheless, while DNA damage and stress responses could be of interest as markers for clin. responses, they have yet to be validated as markers for responses to HDACi treatment in clin. trials, alone, and in combination.
- 43Petruccelli, L. A.; Dupere-Richer, D.; Pettersson, F.; Retrouvey, H.; Skoulikas, S.; Miller, W. H., Jr Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cells. PLoS One 2011, 6, e20987 DOI: 10.1371/journal.pone.0020987[Crossref], [PubMed], [CAS], Google Scholar43https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXnvVSisLg%253D&md5=083e63c00782a7d050d68d5e5b99e487Vorinostat induces reactive oxygen species and DNA damage in acute myeloid leukemia cellsPetruccelli, Luca A.; Dupere-Richer, Daphne; Pettersson, Filippa; Retrouvey, Helene; Skoulikas, Sophia; Miller, Wilson H., Jr.PLoS One (2011), 6 (6), e20987CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Histone deacetylase inhibitors (HDACi) are promising anti-cancer agents, however, their mechanisms of action remain unclear. In acute myeloid leukemia (AML) cells, HDACi have been reported to arrest growth and induce apoptosis. In this study, we elucidate details of the DNA damage induced by the HDACi vorinostat in AML cells. At clin. relevant concns., vorinostat induces double-strand breaks and oxidative DNA damage in AML cell lines. Addnl., AML patient blasts treated with vorinostat display increased DNA damage, followed by an increase in caspase-3/7 activity and a redn. in cell viability. Vorinostat-induced DNA damage is followed by a G2-M arrest and eventually apoptosis. We found that pre-treatment with the antioxidant N-acetyl cysteine (NAC) reduces vorinostat-induced DNA double strand breaks, G2-M arrest and apoptosis. These data implicate DNA damage as an important mechanism in vorinostat-induced growth arrest and apoptosis in both AML cell lines and patient-derived blasts. This supports the continued study and development of vorinostat in AMLs that may be sensitive to DNA-damaging agents and as a combination therapy with ionizing radiation and/or other DNA damaging agents.
- 44Wasim, L.; Chopra, M. Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cells. Biomed. Pharmacother. 2016, 84, 1393– 1405, DOI: 10.1016/j.biopha.2016.10.057[Crossref], [PubMed], [CAS], Google Scholar44https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhslKmsLbE&md5=af85e5121fa4a7de551e5a9a07a75e06Panobinostat induces apoptosis via production of reactive oxygen species and synergizes with topoisomerase inhibitors in cervical cancer cellsWasim, Lubna; Chopra, MadhuBiomedicine & Pharmacotherapy (2016), 84 (), 1393-1405CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Cervical cancer is the fourth major cause of cancer-related deaths in women worldwide and is the most common cancer in developing countries. Therefore, a search for novel treatment modalities is warranted. The present study is designed to investigate the effect of pan histone deacetylase inhibitor, 'panobinostat', on cervical cancer cells alone and in combination with topoisomerase inhibitors. We assessed the effect of panobinostat on two cervical cancer cell lines, HeLa and SiHa, for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. The results indicate that panobinostat reduces the viability of cervical cancer cells in a dose- and time-dependent manner; it arrests HeLa cells in G0/G1 and SiHa cells in G2/M phase of the cell cycle. Panobinostat induced apoptosis through an increase in the ROS prodn. and the disruption of mitochondrial membrane potential. Concomitantly the expression of anti-apoptotic gene Bcl-xL was reduced, while levels of CDK inhibitor p21 and caspase-9 were increased. Panobinostat increased the acetylation of histone H3 indicating HDAC inhibition. In addn., panobinostat also showed synergistic effect with topoisomerase inhibitors mediated by increased activation of caspase-3/7 activity compared to that in cells treated with panobinostat alone. These results suggest a combination therapy using inhibitors of histone deacetylase and topoisomerase together could hold the promise for an effective targeted therapeutic strategy.
- 45Gaymes, T. J.; Padua, R. A.; Pla, M.; Orr, S.; Omidvar, N.; Chomienne, C.; Mufti, G. J.; Rassool, F. V. Histone deacetylase inhibitors (HDI) cause DNA damage in leukemia cells: a mechanism for leukemia-specific HDI-dependent apoptosis?. Mol. Cancer Res. 2006, 4, 563– 573, DOI: 10.1158/1541-7786.MCR-06-0111[Crossref], [PubMed], [CAS], Google Scholar45https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XotV2rt7k%253D&md5=72fe7783bf624402a851a1565cdea3d8Histone Deacetylase Inhibitors (HDI) Cause DNA Damage in Leukemia Cells: A Mechanism for Leukemia-Specific HDI-Dependent Apoptosis?Gaymes, Terry J.; Padua, Rose Ann; Pla, Marika; Orr, Stephen; Omidvar, Nader; Chomienne, Christine; Mufti, Ghulam J.; Rassool, Feyruz V.Molecular Cancer Research (2006), 4 (8), 563-573CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)Histone deacetylase inhibitors (HDI) increase gene expression through induction of histone acetylation. However, it remains unclear whether increases in specific gene expression events det. the apoptotic response following HDI administration. Herein, we show that a variety of HDI trigger in hematopoietic cells not only widespread histone acetylation and DNA damage responses but also actual DNA damage, which is significantly increased in leukemic cells compared with normal cells. Thus, increase in H2AX and ataxia telangiectasia mutated (ATM) phosphorylation, early markers of DNA damage, occurs rapidly following HDI administration. Activation of the DNA damage and repair response following HDI treatment is further emphasized by localizing DNA repair proteins to regions of DNA damage. These events are followed by subsequent apoptosis of neoplastic cells but not normal cells. Our data indicate that induction of apoptosis by HDI may result predominantly through accumulation of excessive DNA damage in leukemia cells, leading to activation of apoptosis.
- 46Yuan, Z.; Chen, S.; Sun, Q.; Wang, N.; Li, D.; Miao, S.; Gao, C.; Chen, Y.; Tan, C.; Jiang, Y. Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapy. Bioorg. Med. Chem. 2017, 25, 4100– 4109, DOI: 10.1016/j.bmc.2017.05.058[Crossref], [PubMed], [CAS], Google Scholar46https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXpslGntbY%253D&md5=ac79d6e4d730eeefc1eda749823c80d5Olaparib hydroxamic acid derivatives as dual PARP and HDAC inhibitors for cancer therapyYuan, Zigao; Chen, Shaopeng; Sun, Qinsheng; Wang, Ning; Li, Dan; Miao, Shuangshuang; Gao, Chunmei; Chen, Yuzong; Tan, Chunyan; Jiang, YuyangBioorganic & Medicinal Chemistry (2017), 25 (15), 4100-4109CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Olaparib was the first PARP inhibitor approved by the FDA for patients with BRCA-mutated ovarian cancer. Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of olaparib and HDAC inhibitors. Herein, based on rational drug design strategy, hydroxamic acid derivs. of olaparib were constructed as dual PARP and HDAC inhibitors. These hybrid compds. showed potent inhibitory activities against PARP1/2 and HDAC1/6 with IC50 values in the nanomolar range. Furthermore, compd. P1 exhibited broad-spectrum antiproliferative activities in selected human cancer cell lines. Specially, P1 showed more potent activity than olaparib and SAHA in cancer cells MDA-MB-231, HCC1937 and Raji, and 4.1-fold less cytotoxicity compared with SAHA to normal cells MCF-10A. Further mechanism study indicated that P1 could induce the cleavage of PARP and the hyperacetylation of histones, increase the expression of DNA damage biomarker γ-H2AX, decrease the level of BRCA1 and RAD51, and regulate tumor cell growth and apoptosis through modulating both mitochondrial- and death receptor-mediated pathways. Therefore, our study suggested that compds. targeting PARP and HDAC concurrently might be a practical approach for cancer therapy.
- 47Konsoula, Z.; Cao, H.; Velena, A.; Jung, M. Adamantanyl-histone deacetylase inhibitor H6CAHA exhibits favorable pharmacokinetics and augments prostate cancer radiation sensitivity. Int. J. Radiat. Oncol., Biol., Phys. 2011, 79, 1541– 1548, DOI: 10.1016/j.ijrobp.2010.11.057[Crossref], [PubMed], [CAS], Google Scholar47https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXjs1SmtLc%253D&md5=223920498e20aede3b56ddc5b35a3768Adamantanyl-Histone Deacetylase Inhibitor H6CAHA Exhibits Favorable Pharmacokinetics and Augments Prostate Cancer Radiation SensitivityKonsoula, Zacharoula; Cao, Hong; Velena, Alfredo; Jung, MiraInternational Journal of Radiation Oncology, Biology, Physics (2011), 79 (5), 1541-1548CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Purpose: To evaluate pharmacol. properties of H6CAHA, an adamantyl-hydroxamate histone deacetylase inhibitor, and to investigate its effect on prostate cancer cells following exposure to γ-radiation in vitro and in vivo. Methods and Materials: H6CAHA was assessed for in vitro soly., lipophilicity and growth inhibition, and in vivo plasma pharmacokinetics. The effect of H6CAHA on radiation clonogenic survival and DNA damage repair was evaluated in human prostate cancer (PC3, DU145, LNCaP) and nonmalignant control epithelial (RWPE1 and 267B1) cell lines. The effect of this agent on the growth of prostate cancer xenografts was also assessed in mice. Results: H6CAHA demonstrated good soly. and permeability profiles and preferentially inhibited the growth of prostate cancer cells over nonmalignant cells. Plasma pharmacokinetics revealed that the area under the curve of H6CAHA was 8.08 ± 0.91 μM × h, and its half-life was 11.17 ± 0.87 h. Radiation clonogenic assays revealed that H6CAHA decreased the survival of prostate cancer cells at the dose that exerted limited effect on normal cells. Concomitantly, delayed DNA damage repair following combination treatment was evident in cancer cells, indicated by the prolonged appearance of γH2AX and Rad51 foci and suppression of DNA damage repair genes (ATM, BRCA1, and BRCA2). Combined modality of H6CAHA (daily i.p. injections for 10 days) with γ-radiation (10 × 2 Gy) completely blocked the growth of PC3 tumor xenografts (p < 0.001) over 60 days. Conclusion: These results support the potential therapeutic value of H6CAHA in combination with radiation and support the rationale for further clin. investigation.
- 48Adimoolam, S.; Sirisawad, M.; Chen, J.; Thiemann, P.; Ford, J. M.; Buggy, J. J. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 19482– 19487, DOI: 10.1073/pnas.0707828104[Crossref], [PubMed], [CAS], Google Scholar48https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXisVOhtQ%253D%253D&md5=09dd875fb60189a663e727ba0e973954HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombinationAdimoolam, Shanthi; Sirisawad, Mint; Chen, Jun; Thiemann, Patti; Ford, James M.; Buggy, Joseph J.Proceedings of the National Academy of Sciences of the United States of America (2007), 104 (49), 19482-19487CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylase (HDAC) inhibitors such as the Ph hydroxamic acid PCI-24781 have emerged recently as a class of therapeutic agents for the treatment of cancer. Recent data showing synergy of HDAC inhibitors with ionizing radiation and other DNA-damaging agents have suggested that HDAC inhibitors may act, in part, by inhibiting DNA repair. Here the authors present evidence that HDAC enzymes are important for homologous recombinational repair of DNA double-strand breaks. Combination studies of PCI-24781 with the poly(ADP-ribose) polymerase inhibitor PJ34, an agent thought to produce lesions repaired by homologous recombination (HR), resulted in a synergistic effect on apoptosis. Immunofluorescence anal. demonstrated that HDAC inhibition caused a complete inhibition of subnuclear repair foci in response to ionizing radiation. Mechanistic investigations revealed that inhibition of HDAC enzymes by PCI-24781 led to a significant redn. in the transcription of genes specifically assocd. with HR, including RAD51. RAD51 protein levels were significantly decreased after 24 h of drug exposure both in vitro and in vivo. Consistent with inhibition of HR, treatment with PCI-24781 resulted in a decreased ability to perform homol. directed repair of I-Scel-induced chromosome breaks in transfected CHO cells. In addn., an enhancement of cell killing was obsd. in Ku mutant cells lacking functional nonhomologous end joining compared with WT cells. Together these results demonstrate that HDAC enzymes are critically important to enable functional HR by controlling the expression of HR-related genes and promoting the proper assembly of HR-directed subnuclear foci.
- 49Munshi, A.; Kurland, J. F.; Nishikawa, T.; Tanaka, T.; Hobbs, M. L.; Tucker, S. L.; Ismail, S.; Stevens, C.; Meyn, R. E. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin. Cancer Res. 2005, 11, 4912– 4922, DOI: 10.1158/1078-0432.CCR-04-2088[Crossref], [PubMed], [CAS], Google Scholar49https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVGgsb8%253D&md5=fb3d905f585b207347b4fc4bf1aecf1eHistone Deacetylase Inhibitors Radiosensitize Human Melanoma Cells by Suppressing DNA Repair ActivityMunshi, Anupama; Kurland, John F.; Nishikawa, Takashi; Tanaka, Toshimitsu; Hobbs, Marvette L.; Tucker, Susan L.; Ismail, Sheikh; Stevens, Craig; Meyn, Raymond E.Clinical Cancer Research (2005), 11 (13), 4912-4922CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)PURPOSE: Histone deacetylase (HDAC) inhibitors have emerged recently as promising anticancer agents. They arrest cells in the cell cycle and induce differentiation and cell death. The antitumor activity of HDAC inhibitors has been linked to their ability to induce gene expression through acetylation of histone and nonhistone proteins. However, it has recently been suggested that HDAC inhibitors may also enhance the activity of other cancer therapeutics, including radiotherapy. The purpose of this study was to evaluate the ability of HDAC inhibitors to radiosensitize human melanoma cells in vitro. Exptl. Design: A panel of HDAC inhibitors that included sodium butyrate (NaB), phenylbutyrate, tributyrin, and trichostatin A were tested for their ability to radiosensitize two human melanoma cell lines (A375 and MeWo) using clonogenic cell survival assays. Apoptosis and DNA repair were measured by std. assays. RESULTS: NaB induced hyperacetylation of histone H4 in the two melanoma cell lines and the normal human fibroblasts. NaB radiosensitized both the A375 and MeWo melanoma cell lines, substantially reducing the surviving fraction at 2 Gy (SF2), whereas it had no effect on the normal human fibroblasts. The other HDAC inhibitors, phenylbutyrate, tributyrin, and trichostatin A had significant radiosensitizing effects on both melanoma cell lines tested. NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as detd. based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examd. γ-H2AX phosphorylation as a marker of radiation response to NaB and obsd. that compared with controls, γ-H2AX foci persisted long after ionizing exposure in the NaB-treated cells. CONCLUSIONS: HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that γ-H2AX phosphorylation can be used as a predictive marker of radioresponse.
- 50Lu, Y. S.; Chou, C. H.; Tzen, K. Y.; Gao, M.; Cheng, A. L.; Kulp, S. K.; Cheng, J. C. Radiosensitizing effect of a phenylbutyrate-derived histone deacetylase inhibitor in hepatocellular carcinoma. Int. J. Radiat. Oncol., Biol., Phys. 2012, 83, e181 DOI: 10.1016/j.ijrobp.2011.12.022[Crossref], [PubMed], [CAS], Google Scholar50https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xjs1agurs%253D&md5=8749674a78d62e0b702dcdb674a1612fRadiosensitizing Effect of a Phenylbutyrate-Derived Histone Deacetylase Inhibitor in Hepatocellular CarcinomaLu, Yen-Shen; Chou, Chia-Hung; Tzen, Kai-Yuan; Gao, Ming; Cheng, Ann-Lii; Kulp, Samuel K.; Cheng, Jason Chia-HsienInternational Journal of Radiation Oncology, Biology, Physics (2012), 83 (2), e181-e189CODEN: IOBPD3; ISSN:0360-3016. (Elsevier Inc.)Radiotherapy is integrated into the multimodal treatment of localized hepatocellular carcinoma (HCC) refractory to conventional treatment. Tumor control remains unsatisfactory and the sublethal effect assocs. with secondary spread. The use of an effective molecularly targeted agent in combination with radiotherapy is a potential therapeutic approach. Our aim was to assess the effect of combining a phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, AR-42, with radiotherapy in in vitro and in vivo models of human HCC. Human HCC cell lines (Huh-7 and PLC-5) were used to evaluate the in vitro synergism of combining AR-42 with irradn. Flow cytometry analyzed the cell cycle changes, whereas Western blot investigated the protein expressions after the combined treatment. Severe combined immunodeficient (SCID) mice bearing ectopic and orthotopic HCC xenografts were treated with AR-42 and/or radiotherapy for the in vivo response. AR-42 significantly enhanced radiation-induced cell death by the inhibition of the DNA end-binding activity of Ku70, a highly versatile regulatory protein for DNA repair, telomere maintenance, and apoptosis. In ectopic xenografts of Huh-7 and PLC-5, pretreatment with AR-42 significantly enhanced the tumor-suppressive effect of radiotherapy by 48% and 66%, resp. A similar combinatorial effect of AR-42 (10 and 25 mg/kg) and radiotherapy was obsd. in Huh-7 orthotopic model of tumor growth by 52% and 82%, resp. This tumor suppression was assocd. with inhibition of intratumoral Ku70 activity as well as redns. in markers of HDAC activity and proliferation, and increased apoptosis. AR-42 is a potent, orally bioavailable inhibitor of HDAC with therapeutic value as a radiosensitizer of HCC.
- 51Butler, L. M.; Zhou, X.; Xu, W. S.; Scher, H. I.; Rifkind, R. A.; Marks, P. A.; Richon, V. M. The histone deacetylase inhibitor SAHA arrests cancer cell growth, upregulates thioredoxin-binding protein-2 and downregulates thioredoxin. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 11700– 11705, DOI: 10.1073/pnas.182372299[Crossref], [PubMed], [CAS], Google Scholar51https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XntFWqsbY%253D&md5=5930aacd5ff4ac0383fadf84cbf1d98eThe histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxinButler, Lisa M.; Zhou, Xianbo; Xu, Wei-Sheng; Scher, Howard I.; Rifkind, Richard A.; Marks, Paul A.; Richon, Victoria M.Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (18), 11700-11705CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clin. trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-upregulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.
- 52Deroanne, C. F.; Bonjean, K.; Servotte, S.; Devy, L.; Colige, A.; Clausse, N.; Blacher, N.; Verdin, E.; Foidart, J. M.; Nusgens, B. V.; Castronovo, V. Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling. Oncogene 2002, 21, 427– 436, DOI: 10.1038/sj.onc.1205108[Crossref], [PubMed], [CAS], Google Scholar52https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XhtVygtL4%253D&md5=6c29afb901cdf1ee5a31b144199b4e36Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signalingDeroanne, Christophe F.; Bonjean, Karine; Servotte, Sandrine; Devy, Laetitia; Colige, Alain; Clausse, Nathalie; Blacher, Sylvia; Verdin, Eric; Foidart, Jean-Michel; Nusgens, Betty V.; Castronovo, VincentOncogene (2002), 21 (3), 427-436CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)Angiogenesis is a complex biol. process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-pos. capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relation, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not obsd. in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling.
- 53Hutt, D. M.; Roth, D. M.; Vignaud, H.; Cullin, C.; Bouchecareilh, M. The histone deacetylase inhibitor, Vorinostat, represses hypoxia inducible factor 1 alpha expression through translational inhibition. PLoS One 2014, 9, e106224 DOI: 10.1371/journal.pone.0106224
- 54Kim, M. S.; Kwon, H. J.; Lee, Y. M.; Baek, J. H.; Jang, J. E.; Lee, S. W.; Moon, E. J.; Kim, H. S.; Lee, S. K.; Chung, H. Y.; Kim, C. W.; Kim, K. W. Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat. Med. 2001, 7, 437– 443, DOI: 10.1038/86507[Crossref], [PubMed], [CAS], Google Scholar54https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXis1yks7s%253D&md5=cd7462043c77421e07b4c148207267c9Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genesKim, Myoung Sook; Kwon, Ho Jeong; Lee, You Mie; Baek, Jin Hyen; Jang, Jae-Eun; Lee, Sae-Won; Moon, Eun-Joung; Kim, Hae-Sun; Lee, Seok-Ki; Chung, Hae Young; Kim, Chul Woo; Kim, Kyu-WonNature Medicine (New York, NY, United States) (2001), 7 (4), 437-443CODEN: NAMEFI; ISSN:1078-8956. (Nature America Inc.)Low oxygen tension influences tumor progression by enhancing angiogenesis; and histone deacetylases (HDAC) are implicated in alteration of chromatin assembly and tumorigenesis. Here we show induction of HDAC under hypoxia and elucidate a role for HDAC in the regulation of hypoxia-induced angiogenesis. Overexpressed wild-type HDAC1 downregulated expression of p53 and von Hippel-Lindau tumor suppressor genes and stimulated angiogenesis of human endothelial cells. A specific HDAC inhibitor, trichostatin A (TSA), upregulated p53 and von Hippel-Lindau expression and downregulated hypoxia-inducible factor-1α and vascular endothelial growth factor. TSA also blocked angiogenesis in vitro and in vivo. TSA specifically inhibited hypoxia-induced angiogenesis in the Lewis lung carcinoma model. These results indicate that hypoxia enhances HDAC function and that HDAC is closely involved in angiogenesis through suppression of hypoxia-responsive tumor suppressor genes.
- 55Crazzolara, R.; Jöhrer, K.; Johnstone, R. W.; Greil, R.; Ofler, R.; Meister, B.; Bernhard, D. Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukaemia. Br. J. Haematol. 2002, 119, 965– 969, DOI: 10.1046/j.1365-2141.2002.03955.x[Crossref], [PubMed], [CAS], Google Scholar55https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXnt12nuw%253D%253D&md5=0c5b12b74a00b150900e421a9e2ad1c6Histone deacetylase inhibitors potently repress CXCR4 chemokine receptor expression and function in acute lymphoblastic leukemiaCrazzolara, Roman; Johrer, Karin; Johnstone, Ricky W.; Greil, Richard; Kofler, Reinhard; Meister, Bernhard; Bernhard, DavidBritish Journal of Haematology (2002), 119 (4), 965-969CODEN: BJHEAL; ISSN:0007-1048. (Blackwell Science Ltd.)The chemokine receptor CXCR4 plays a crucial role in the survival and trafficking of leukemia cells and requires further attention as human immunodeficiency virus type I (HIV-I) utilizes CXCR4 as the major coreceptor for cellular entry. We demonstrated that inhibitors of histone deacetylases, currently being tested in clin. trials for the treatment of various tumors, extensively downregulated CXCR4 protein and mRNA levels in leukemia cell lines and lymphoblasts from patients with childhood acute leukemia. As a result, the ability of stromal cell-derived factor-1 to induce cellular migration was impaired. Repression of CXCR4 transcription by inhibitors of histone deacetylases might therefore represent a promising novel approach in the treatment of acute leukemias.
- 56Magner, W. J.; Kazim, A. L.; Stewart, C.; Romano, M. A.; Catalano, G.; Grande, C.; Keiser, N.; Santaniello, F.; Tomasi, B. T. Activation of MHC class I, II and CD40 gene expression by histone deacetylase inhibitors. J. Immunol. 2000, 165, 7017– 7024, DOI: 10.4049/jimmunol.165.12.7017[Crossref], [PubMed], [CAS], Google Scholar56https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXovFygsrs%253D&md5=99a484093103f963af0075000758055eActivation of MHC class I, II, and CD40 gene expression by histone deacetylase inhibitorsMagner, William J.; Kazim, A. Latif; Stewart, Carleton; Romano, Michelle A.; Catalano, Geoffrey; Grande, Catherine; Keiser, Nicholas; Santaniello, Frank; Tomasi, Thomas B.Journal of Immunology (2000), 165 (12), 7017-7024CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)Epigenetic mechanisms are involved in regulating chromatin structure and gene expression through repression. In this study, we show that histone deacetylase inhibitors (DAIs) that alter the acetylation of histones in chromatin enhance the expression of several genes on tumor cells including: MHC class I, II, and the costimulatory mol. CD40. Enhanced transcription results in a significant increase in protein expression on the tumor cell surface, and expression can be elicited on some tumors that are unresponsive to IFN-γ. The magnitude of induction of these genes cannot be explained by the effect of DAIs on the cell cycle or enhanced apoptosis. Induction of class II genes by DAIs was accompanied by activation of a repressed class II transactivator gene in a plasma cell tumor but, in several other tumor cell lines, class II was induced in the apparent absence of class II transactivator transcripts. These findings also suggest that the abnormalities obsd. in some tumors in the expression of genes crit. to tumor immunity may result from epigenetic alterations in chromatin and gene regulation in addn. to well-established mutational mechanisms.
- 57Maeda, T.; Towatari, M.; Kosugi, H.; Saito, H. Up-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cells. Blood 2000, 96, 3847– 3856, DOI: 10.1182/blood.V96.12.3847[Crossref], [PubMed], [CAS], Google Scholar57https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3cXosVGntbk%253D&md5=1f6dd50e56a0c4104447a3243de5627dUp-regulation of costimulatory/adhesion molecules by histone deacetylase inhibitors in acute myeloid leukemia cellsMaeda, Takahiro; Towatari, Masayuki; Kosugi, Hiroshi; Saito, HidehikoBlood (2000), 96 (12), 3847-3856CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)Histone deacetylase inhibitors (HDACIs) have been used to focus on the effects of inducing gene expression through the acetylation of histones which results in chromatin remodeling. The study explored whether HDACIs could induce the expression of costimulatory/adhesion mols. on acute myeloid leukemia (AML) cells, thereby effectively inducing tumor immunity. The expression of CD80, CD86, human leukocyte antigen (HLA)-DR, HLA-ABC, and intracellular adhesion mol.-1 (ICAM-1) was tested in human AML cell lines after the addn. of HDACI, sodium butyrate (SB). Generally, increased expression of CD86 was obsd. by SB treatment in a majority of cell lines, and ICAM-1 was expressed in fewer cell lines. Essentially the same results were obtained using other HDACIs such as FR901228, trichostatin A, and trapoxin A. Quantitation of transcripts of CD86 accompanied with RNA synthesis inhibition assay and nuclear run-on assay revealed that SB up-regulates the CD86 expression transcriptionally. Furthermore, chromatin immunopptn. expts. showed that HDACI treatment caused remarkable acetylation on histone H3 and H4 at CD86 promoter chromatin in vivo. In 30 clin. AML samples, CD86 expression was significantly increased (P <.001) by SB treatment, and the expression of HLA-DR and ICAM-1 was moderately increased (P <.05) by SB treatment. Finally, the allogeneic mixed leukocyte reaction (allo-MLR) against HL60 cells pretreated with SB was enhanced 4-fold compared with allo-MLR obtained with non-treated HL60 cells. These results suggest that the immunotherapeutic use of HDACIs may become a novel tool for treatment of AML.
- 58Li, S.; Fossati, G.; Marchetti, C.; Modena, D.; Pozzi, P.; Reznikov, L. L.; Moras, M. L.; Azam, T.; Abbate, A.; Mascagni, P.; Dinarello, C. A. Specific inhibition of histone deacetylase 8 reduces gene expression and production of proinflammatory cytokines in vitro and in vivo. J. Biol. Chem. 2015, 290, 2368– 2378, DOI: 10.1074/jbc.M114.618454[Crossref], [PubMed], [CAS], Google Scholar58https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCqtbs%253D&md5=1af57c4a219c0636e77fa1be3f7a98b4Specific Inhibition of Histone Deacetylase 8 Reduces Gene Expression and Production of Proinflammatory Cytokines in Vitro and in VivoLi, Suzhao; Fossati, Gianluca; Marchetti, Carlo; Modena, Daniela; Pozzi, Pietro; Reznikov, Leonid L.; Moras, Maria Luisa; Azam, Tania; Abbate, Antonio; Mascagni, Paolo; Dinarello, Charles A.Journal of Biological Chemistry (2015), 290 (4), 2368-2378CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)ITF2357 (generic givinostat) is an orally active, hydroxamic-contg. histone deacetylase (HDAC) inhibitor with broad anti-inflammatory properties, which has been used to treat children with systemic juvenile idiopathic arthritis. ITF2357 inhibits both Class I and II HDACs and reduces caspase-1 activity in human peripheral blood mononuclear cells and the secretion of IL-1β and other cytokines at 25-100 nm; at concns. >200 nm, ITF2357 is toxic in vitro. ITF3056, an analog of ITF2357, inhibits only HDAC8 (IC50 of 285 nm). Here we compared the prodn. of IL-1β, IL-1α, TNFα, and IL-6 by ITF2357 with that of ITF3056 in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS), heat-killed Candida albicans, or anti-CD3/anti-CD28 antibodies. ITF3056 reduced LPS-induced cytokines from 100 to 1000 nm; at 1000 nm, the secretion of IL-1β was reduced by 76%, secretion of TNFα was reduced by 88%, and secretion of IL-6 was reduced by 61%. The intracellular levels of IL-1α were 30% lower. There was no evidence of cell toxicity at ITF3056 concns. of 100-1000 nm. Gene expression of TNFα was markedly reduced (80%), whereas IL-6 gene expression was 40% lower. Although anti-CD3/28 and Candida stimulation of IL-1β and TNFα was modestly reduced, IFNγ prodn. was 75% lower. Mechanistically, ITF3056 reduced the secretion of processed IL-1β independent of inhibition of caspase-1 activity; however, synthesis of the IL-1β precursor was reduced by 40% without significant decrease in IL-1β mRNA levels. In mice, ITF3056 reduced LPS-induced serum TNFα by 85% and reduced IL-1β by 88%. These data suggest that specific inhibition of HDAC8 results in reduced inflammation without cell toxicity.
- 59Leoni, F.; Zaliani, A.; Bertolini, G.; Porro, G.; Pagani, P.; Pozzi, P.; Donà, G.; Fossati, G.; Sozzani, S.; Azam, T.; Bufler, P.; Fantuzzi, G.; Goncharov, I.; Kim, S. H.; Pomerantz, B. J.; Reznikov, L. L.; Siegmund, B.; Dinarello, C. A.; Mascagni, P. The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokines. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 2995– 3000, DOI: 10.1073/pnas.052702999[Crossref], [PubMed], [CAS], Google Scholar59https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xit1Cru78%253D&md5=f3d5aa94ba911a071246527199c563aeThe antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits antiinflammatory properties via suppression of cytokinesLeoni, Flavio; Zaliani, Andrea; Bertolini, Giorgio; Porro, Giulia; Pagani, Paolo; Pozzi, Pietro; Dona, Giancarlo; Fossati, Gianluca; Sozzani, Silvano; Azam, Tania; Bufler, Philip; Fantuzzi, Giamila; Goncharov, Igor; Kim, Soo-Hyun; Pomerantz, Benjamin J.; Reznikov, Leonid L.; Siegmund, Britta; Dinarello, Charles A.; Mascagni, PaoloProceedings of the National Academy of Sciences of the United States of America (2002), 99 (5), 2995-3000CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Suberoylanilide hydroxamic acid (SAHA) is a hydroxamic acid-contg. hybrid polar mol.; SAHA specifically binds to and inhibits the activity of histone deacetylase. Although SAHA, like other inhibitors of histone deacetylase, exhibits antitumor effects by increasing expression of genes regulating tumor survival, we found that SAHA reduces the prodn. of proinflammatory cytokines in vivo and in vitro. A single oral administration of SAHA to mice dose-dependently reduced circulating TNF-α, IL-1β, IL-6, and IFN-γ induced by lipopolysaccharide (LPS). Administration of SAHA also reduced hepatic cellular injury in mice following i.v. injection of Con A. SAHA inhibited nitric oxide release in mouse macrophages stimulated by the combination of TNF-α plus IFN-γ. Human peripheral blood mononuclear cells stimulated with LPS in the presence of SAHA released less TNF-α, IL-1β, IL-12, and IFN-γ (50% redn. at 100-200 nM). The prodn. of IFN-γ stimulated by IL-18 plus IL-12 was also inhibited by SAHA (85% at 200 nM). However, SAHA did not affect LPS-induced synthesis of the IL-1β precursor, the IL-1 receptor antagonist, or the chemokine IL-8. In addn., IFN-γ induced by anti-CD3 was not suppressed by SAHA. Steady-state mRNA levels for LPS-induced TNF-α and IFN-γ in peripheral blood mononuclear cells were markedly decreased, whereas IL-8 and IL-1β mRNA levels were unaffected. Because SAHA exhibits antiinflammatory properties in vivo and in vitro, inhibitors of histone deacetylase may stimulate the expression of genes that control the synthesis of cytokines and nitric oxide or hyper-acetylate other targets.
- 60Shao, Y.; Gao, Z.; Marks, P. A.; Jiang, X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 18030– 18035, DOI: 10.1073/pnas.0408345102[Crossref], [PubMed], [CAS], Google Scholar60https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsl2nsQ%253D%253D&md5=50d75dc3fafd03181c5d19365d2b605fApoptotic and autophagic cell death induced by histone deacetylase inhibitorsShao, Yufang; Gao, Zhonghua; Marks, Paul A.; Jiang, XuejunProceedings of the National Academy of Sciences of the United States of America (2004), 101 (52), 18030-18035CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylase (HDAC) inhibitors can induce programmed cell death in cancer cells, although the underlying mechanism is obscure. In this study, we show that two distinct HDAC inhibitors, butyrate and suberoylanilide hydroxamic acid (SAHA), induced caspase-3 activation and cell death in multiple human cancer cell lines. The activation of caspase-3 was via the mitochondria/cytochrome c-mediated apoptotic pathway because it was abrogated in mouse embryonic fibroblasts with knockout of Apaf-1, the essential mediator of the pathway. Overexpression of Bcl-XL in HeLa cells also blocked caspase activation by the HDAC inhibitors. Nevertheless, Apaf-1 knockout, overexpression of Bcl-XL, and pharmacol. inhibition of caspase activity did not prevent SAHA and butyrate-induced cell death. The cells undergoing such caspase-independent death had unambiguous morphol. features of autophagic cell death. Therefore, HDAC inhibitors can induce both mitochondria-mediated apoptosis and caspase-independent autophagic cell death. Induction of autophagic cell death by HDAC inhibitors has clear clin. implications in treating cancers with apoptotic defects.
- 61Condorelli, F.; Gnemmi, I.; Vallario, A.; Genazzani, A. A.; Canonico, P. L. Inhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cells. Br. J. Pharmacol. 2008, 153, 657– 668, DOI: 10.1038/sj.bjp.0707608[Crossref], [PubMed], [CAS], Google Scholar61https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXitVKjsr8%253D&md5=afb61167f7671c707f498c8b571b736dInhibitors of histone deacetylase (HDAC) restore the p53 pathway in neuroblastoma cellsCondorelli, F.; Gnemmi, I.; Vallario, A.; Genazzani, A. A.; Canonico, P. L.British Journal of Pharmacology (2008), 153 (4), 657-668CODEN: BJPCBM; ISSN:0007-1188. (Nature Publishing Group)Inhibitors of histone deacetylase (HDAC) are emerging as a promising class of anti-cancer drugs, but a generic deregulation of transcription in neoplastic cells cannot fully explain their therapeutic effects. In this study we evaluated alternative mol. mechanisms by which HDAC inhibitors could affect neuroblastoma viability. Effects of HDAC inhibitors on survival of the I-type SK-N-BE and the N-type NB SH-SY5Y neuroblastoma cell lines were assessed by the MTT assay. Mol. pathways leading to this were examd. by western blot, confocal microscopy and cytofluorometry. The mRNA levels of apoptotic mediators were assessed semi-quant. by RT-PCR. Tumor-suppressor p53 trans activity was assessed in EMSA expts. HDAC inhibitors were also studied in cells subjected to plasmid-based p53 interference (p53i). HDAC inhibitors induced cell death via the mitochondrial pathway of apoptosis with recruitment of Bcl-2 family members. Bcl-2 overexpression rendered neuroblastoma cells resistant to HDAC inhibitor treatment. Low concns. of HDAC inhibitors (0.9 m) caused a G2 cell-cycle arrest and a marked upregulation of the p21/Waf1/Cip1 protein. HDAC inhibitors also activate the p53 protein via hyper-acetylation and nuclear re-localization, without affecting its protein expression. Accordingly, HDAC inhibitor-induced cell-killing and p21/Waf1/Cip1 upregulation is impaired in p53i-cells. In neuroblastoma cells, HDAC inhibitors may overcome the resistance to classical chemotherapeutic drugs by restoring the p53 tumor-repressor function via its hyper-acetylation and nuclear migration, events usually impaired in such tumors. In neuroblastoma cells, HDAC inhibitors are not able to induce p21/Waf1/Cip1 in the absence of a functional p53.
- 62Li, Z. Y.; Li, Q. Z.; Chen, L.; Chen, B. D.; Wang, B.; Zhang, X. J.; Li, W. P. Histone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance by Blocking NF-κB-Dependent Transcription in Glioblastoma Cell Lines. Neurochem. Res. 2016, 41, 3192– 3205, DOI: 10.1007/s11064-016-2043-5[Crossref], [PubMed], [CAS], Google Scholar62https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVyksL7K&md5=f332f2ea76c8170814d0b8432cdc028eHistone Deacetylase Inhibitor RGFP109 Overcomes Temozolomide Resistance by Blocking NF-κB-Dependent Transcription in Glioblastoma Cell LinesLi, Zong-yang; Li, Qing-zhong; Chen, Lei; Chen, Bao-dong; Wang, Bo; Zhang, Xie-jun; Li, Wei-pingNeurochemical Research (2016), 41 (12), 3192-3205CODEN: NEREDZ; ISSN:0364-3190. (Springer)Glioblastoma (GBM) is the most frequent and aggressive tumor in the central nervous system. Many studies have demonstrated that upregulation of the NF-κB onco-pathway is accompanied by the acquisition of Temozolomide (TMZ) resistance in GBM cells. Here, we show that RGFP109, a selective histone deacetylase (HDAC1 and HDAC3) inhibitor, overcomes TMZ resistance and downregulates the expression of NF-κB-regulated pro-survival genes in a TMZ-resistant (TR) GBM cell line. RGFP109 did not alter the phosphorylation levels of NF-κB/p65 or inhibitory κBα (IκBα). Immunofluorescence microscopy showed that RGFP109 does not block the nuclear translocation of NF-κB/p65. However, co-immunopptn. assays revealed that RGFP109 induces the hyperacetylation of NF-κB/p65 and histones, and blocks interactions between NF-κB/p65 and its coactivators, p300 and p300/CBP-assocd. factor (PCAF). These results indicate that RGFP109-mediated post-translational nuclear acetylation may be involved in the regulation of NF-κB. Electrophoretic mobility shift assays revealed that RGFP109 reduces NF-κB/p65 binding to κB-DNA and decreased the transcriptional level of κB-mediated genes, suggesting that RGFP109-induced hyperacetylation leads to attenuated transcription of the κB gene. In addn., RGFP109 elevates the expression of inhibitor of growth 4 (ING4), which is typically downregulated in GBM cells. Importantly, we found that RGFP109 enhances ING4 recognition and binding to NF-κB/p65, which may be pos. correlated with reduced interactions between NF-κB/p65 and p300/PCAF, thereby effecting transcription of the κB gene. Finally, we show that knockdown of ING4 with plasmids contg. pcDNA3.1-ING4 shRNA abolished the effect of RGFP109. Therefore, ING4 may act as a corepressor and facilitate RGFP109-triggered suppression of the NF-κB pathway. Taken together, our data show that RGFP109, an HDAC inhibitor, in combination with TMZ may be a therapeutic candidate for patients with temozolomide-resistant GBM.
- 63Vishwakarma, S.; Iyer, L. R.; Muley, M.; Singh, P. K.; Shastry, A.; Saxena, A.; Kulathingal, J.; Vijaykanth, G.; Raghul, J.; Rajesh, N.; Rathinasamy, S.; Kachhadia, V.; Kilambi, N.; Rajgopal, S.; Balasubramanian, G.; Narayanan, S. Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effects. Int. Immunopharmacol. 2013, 16, 72– 78, DOI: 10.1016/j.intimp.2013.03.016[Crossref], [PubMed], [CAS], Google Scholar63https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXntlWjsr4%253D&md5=1810b101113330405d3923cbadb628b7Tubastatin, a selective histone deacetylase 6 inhibitor shows anti-inflammatory and anti-rheumatic effectsVishwakarma, Santosh; Iyer, Lakshmi R.; Muley, Milind; Singh, Pankaj Kumar; Shastry, Arun; Saxena, Ambrish; Kulathingal, Jayanarayan; Vijaykanth, G.; Raghul, J.; Rajesh, Navin; Rathinasamy, Suresh; Kachhadia, Virendra; Kilambi, Narasimhan; Rajgopal, Sridharan; Balasubramanian, Gopalan; Narayanan, ShridharInternational Immunopharmacology (2013), 16 (1), 72-78CODEN: IINMBA; ISSN:1567-5769. (Elsevier B.V.)Epigenetic modifications represent a promising new approach to modulate cell functions as obsd. in autoimmune diseases. Emerging evidence suggests the utility of HDAC inhibitors in the treatment of chronic immune and inflammatory disorders. However, class and isoform selective inhibition of HDAC is currently favored as it limits the toxicity that was obsd. with pan-HDAC inhibitors. HDAC6, a member of the HDAC family, whose major substrate is α-tubulin, is being increasingly implicated in the pathogenesis of inflammatory disorders. The present study was carried out to study the potential anti-inflammatory and anti-rheumatic effects of HDAC6 selective inhibitor Tubastatin. Tubastatin, a potent human HDAC6 inhibitor with an IC50 of 11 nM showed significant inhibition of TNF-α and IL-6 in LPS stimulated human THP-1 macrophages with an IC50 of 272 nM and 712 nM, resp. Addnl., Tubastatin inhibited NO secretion in murine Raw 264.7 macrophages dose dependently with an IC50 of 4.2 μM and induced α-tubulin hyperacetylation corresponding to HDAC6 inhibition in THP-1 cells without affecting the cell viability. Tubastatin showed significant inhibition of paw vol. at 30 mg/kg i.p. in a Freund's complete adjuvant (FCA) induced animal model of inflammation. The disease modifying activity of Tubastatin was also evident in collagen induced arthritis DBA1 mouse model at 30 mg/kg i.p. The significant attenuation of clin. scores (∼ 70%) by Tubastatin was confirmed histopathol. and was found comparable to dexamethasone (∼ 90% inhibition of clin. scores). Tubastatin showed significant inhibition of IL-6 in paw tissues of arthritic mice. The present work has demonstrated anti-inflammatory and antirheumatic effects of a selective HDAC6 inhibitor Tubastatin.
- 64Leng, C.; Gries, M.; Ziegler, J.; Lokshin, A.; Mascagni, P.; Lentzsch, S.; Mapara, M. Y. Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp. Hematol. 2006, 34, 776– 787, DOI: 10.1016/j.exphem.2006.02.014[Crossref], [PubMed], [CAS], Google Scholar64https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XkvVyntLY%253D&md5=8f028bebfb0a4ca6198545fff17efa95Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1Leng, Corinna; Gries, Margarethe; Ziegler, Judy; Lokshin, Anna; Mascagni, Paolo; Lentzsch, Suzanne; Mapara, Markus Y.Experimental Hematology (New York, NY, United States) (2006), 34 (6), 776-787CODEN: EXHMA6; ISSN:0301-472X. (Elsevier Inc.)Histone deacetylase (HDAC) inhibitors reduce development of graft-vs.-host disease (GVHD) following allogeneic bone marrow transplantation (BMT). Administration of the HDAC inhibitor suberonylanilide hydroxamic acid (SAHA) resulted in a significantly reduced GVHD-dependent mortality following fully major histocompatibility complex-mismatched allogeneic BMT. However, SAHA treatment did not affect T-cell activation or T-cell expansion in vitro and in vivo. Therefore, we focused on the effects of SAHA treatment on cytokine prodn. and intracellular signaling events in vitro and in vivo following GVHD induction. Cultivation in the presence of SAHA broadly inhibited lipopolysaccharide (LPS) and alloantigen-induced cytokine/chemokine prodn. in vitro and led also to a significant decrease in interferon-γ and tumor necrosis factor-α levels in vivo following induction of GVHD. Concomitantly, SAHA treatment inhibited phosphorylation of STAT1 and STAT3 in response to LPS and alloactivation in vitro. Induction of GVHD led to a rapid phosphorylation of STAT 1 in the liver and spleen, which was markedly reduced by SAHA treatment. In conclusion, GVHD is assocd. with a marked induction of phosphorylation of STAT1 in the liver and spleen, and SAHA-dependent redn. of GVHD is assocd. with systemic and local inhibition of phosphorylated STAT1 and blunting proinflammatory cytokine prodn. during the initiation phase of GVHD.
- 65Chen, J.; Li, N.; Liu, B.; Ling, J.; Yang, W.; Pang, X.; Li, T. Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathways. Life Sci. 2020, 248, 117469, DOI: 10.1016/j.lfs.2020.117469[Crossref], [PubMed], [CAS], Google Scholar65https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXlt1ersbo%253D&md5=27ee9f16af9375ba31a37612136d8ff4Pracinostat (SB939), a histone deacetylase inhibitor, suppresses breast cancer metastasis and growth by inactivating the IL-6/STAT3 signalling pathwaysChen, Jing; Li, Na; Liu, Boxia; Ling, Jun; Yang, Wenjun; Pang, Xiufeng; Li, TaoLife Sciences (2020), 248 (), 117469CODEN: LIFSAK; ISSN:0024-3205. (Elsevier B.V.)Histone deacetylases inhibitors have shown favorable antitumor activity in clin. investigations. In the present study, we assessed the effects of a novel hydroxamic acid-based HDAC inhibitor, SB939, on breast cancer metastasis and tumor growth and characterized the underlying mol. mechanisms. MTS, Wound-healing, and Transwell chamber invasion assays were used to detect the inhibition effects of SB939 on proliferation, migration, and invasion of breast cancer cells. Western blot, cellular immunofluorescence, and EMSA were used to explore the mol. mechanism of SB939 in suppressing breast cancer metastasis. MDA-MB-231 s.c. tumor-bearing model of nude mice and the spontaneous metastasis model of breast cancer were both applied to verify in vivo anti-tumor growth and anti-metastatic effects. Our results demonstrated that SB939 at 0.5-1μmol/L markedly impaired the chemotactic motility of breast cancer cells. SB939 reversed epithelial-mesenchymal transition (EMT) process, as evidenced by upregulation E-cadherin expression and downregulation expressions of N-cadherin and vimentin through increasing the levels of ac-histone H3 and H4 and drecreasing the expressiongs of HDAC 5 and 4. This cascade inhibition mediated by SB939 was well interpreted by inactivating phosphorylation of STAT3, blocking its DNA-binding activity, and decreasing the expressions of STAT3-dependent target genes, including MMP2 and MMP9. Furhtermore, we found that SB939 significantly inhibited breast cancer metastasis and tumor growth in vivo and showed superior anti-tumor properties compared with SAHA in two breast cancer animal models. Our findings indicate that SB939 may be an effective therapeutic option for treating advanced breast cancer.
- 66Pinz, S.; Unser, S.; Buob, D.; Fischer, P.; Jobst, B.; Rascle, A. Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein function. Nucleic Acids Res. 2015, 43, 3524– 3545, DOI: 10.1093/nar/gkv188[Crossref], [PubMed], [CAS], Google Scholar66https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsFaisbjE&md5=b97274a797559912f296ab19fd7975e9Deacetylase inhibitors repress STAT5-mediated transcription by interfering with bromodomain and extra-terminal (BET) protein functionPinz, Sophia; Unser, Samy; Buob, Dominik; Fischer, Philipp; Jobst, Belinda; Rascle, AnneNucleic Acids Research (2015), 43 (7), 3524-3545CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)Signal transducer and activator of transcription STAT5 is essential for the regulation of proliferation and survival genes. Its activity is tightly regulated through cytokine signaling and is often upregulated in cancer. The authors showed previously that the deacetylase inhibitor trichostatin A (TSA) inhibits STAT5-mediated transcription by preventing recruitment of the transcriptional machinery at a step following STAT5 binding to DNA. The mechanism and factors involved in this inhibition remain unknown. The authors now show that deacetylase inhibitors do not target STAT5 acetylation, as the authors initially hypothesized. Instead, they induce a rapid increase in global histone acetylation apparently resulting in the delocalization of the bromodomain and extra-terminal (BET) protein Brd2 and of the Brd2-assocd. factor TBP to hyperacetylated chromatin. Treatment with the BET inhibitor (+)-JQ1 inhibited expression of STAT5 target genes, supporting a role of BET proteins in the regulation of STAT5 activity. Accordingly, chromatin immunopptn. demonstrated that Brd2 is assocd. with the transcriptionally active STAT5 target gene Cis and is displaced upon TSA treatment. The authors' data therefore indicate that Brd2 is required for the proper recruitment of the transcriptional machinery at STAT5 target genes and that deacetylase inhibitors suppress STAT5-mediated transcription by interfering with Brd2 function.
- 67Rascle, A.; Johnston, J. A.; Amati, B. Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5. Mol. Cell. Biol. 2003, 23, 4162– 4173, DOI: 10.1128/MCB.23.12.4162-4173.2003[Crossref], [PubMed], [CAS], Google Scholar67https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXks1ykurs%253D&md5=11bf35b090b67fe97b668fa11a410415Deacetylase activity is required for recruitment of the basal transcription machinery and transactivation by STAT5Rascle, Anne; Johnston, James A.; Amati, BrunoMolecular and Cellular Biology (2003), 23 (12), 4162-4173CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The signal transducer and activator of transcription STAT5 plays a major role in the cellular response to cytokines, but the mechanism by which it activates transcription remains poorly understood. We show here that deacetylase inhibitors (trichostatin A, suberoylanilide hydroxamic acid, and sodium butyrate) prevent induction of endogenous STAT5 target genes, implying that a deacetylase activity is required for that process. Microarray analyses revealed that this requirement is common to all STAT5 target genes. Using chromatin immunopptn., we show that, following STAT5 DNA binding, deacetylase inhibitors block transcription initiation by preventing recruitment of the basal transcription machinery. This inhibition is not due to effects on histone H3 and H4 acetylation or chromatin remodeling within the promoter region. This novel mechanism of transactivation by STAT5 provides a rationale for the use of deacetylase inhibitors for therapeutic intervention in STAT5-assocd. cancers.
- 68He, B.; Dai, L.; Zhang, X.; Chen, D.; Wu, J.; Feng, X.; Zhang, Y.; Xie, H.; Zhou, L.; Wu, J.; Zheng, S. The HDAC inhibitor quisinostat (JNJ-26481585) supresses hepatocellular carcinoma alone and synergistically in combination with sorafenib by G0/G1 phase arrest and apoptosis induction. Int. J. Biol. Sci. 2018, 14, 1845– 1858, DOI: 10.7150/ijbs.27661[Crossref], [PubMed], [CAS], Google Scholar68https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsFSntLbN&md5=3cab5f9dde8ea91a491a2381af18f050The HDAC inhibitor quisinostat (JNJ-26481585) suppresses hepatocellular carcinoma alone and synergistically in combination with sorafenib by G0/G1 phase arrest and apoptosis inductionHe, Bin; Dai, Longfei; Zhang, Xiaoqian; Chen, Diyu; Wu, Jingbang; Feng, Xiaode; Zhang, Yanpeng; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, ShusenInternational Journal of Biological Sciences (2018), 14 (13), 1845-1858CODEN: IJBSB9; ISSN:1449-2288. (Ivyspring International Publisher)In our study, we evaluated effect of quisinostat alone and in combination with sorafenib in HCC cells via inducing G0/G1 phase arrest through PI3K/AKT/p21 pathway and apoptosis by JNK/c-Jun/caspase3 pathway in vitro and in vivo. The proliferation assay and flow cytometry were used to measure the viability, cell cycle and apoptosis. Here, we found that quisinostat impeded cell proliferation, and remarkably induced G0/G1 phase arrest and apoptosis in HCC cells in a dose-dependent manner. G0/G1 phase arrest was obsd. by alterations in PI3K/AKT/p21 proteins. Meanwhile the JNK, c-jun and caspase-3 were activated by quisinostat in a dose-dependent manner. Correspondingly quisinostat facilitated G0/G1 cycle arrest and apoptosis in HCC cells through PI3K/AKT/p21 pathways and JNK/c- jun/caspase3 pathways. Moreover, the potent tumor-suppressive effects facilitated by quisinostat, was significantly potentiated by combination with sorafenib in vitro and vivo. The combination treatment of quisinostat and sorafenib markedly suppressed cell proliferation and induced apoptosis in a synergistic manner. Our study indicated that quisinostat, as a novel chemotherapy for HCC, exhibited excellent antitumor activity in vitro and vivo, which was even enhanced by the addn. of sorafenib, implying combination of quisinostat with sorafenib a promising and alternative therapy for patients with advanced hepatocellular carcinoma.
- 69Sharma, V.; Koul, N.; Joseph, C.; Dixit, D.; Ghosh, S.; Sen, E. HDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activity. J. Cell. Mol. Med. 2010, 14, 2151– 2561, DOI: 10.1111/j.1582-4934.2009.00844.x[Crossref], [PubMed], [CAS], Google Scholar69https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVahu77P&md5=b10dea0614f7fa1a5724e4b9129ea63eHDAC inhibitor, scriptaid, induces glioma cell apoptosis through JNK activation and inhibits telomerase activitySharma, Vivek; Koul, Nitin; Joseph, Christy; Dixit, Deobrat; Ghosh, Sadashib; Sen, ElloraJournal of Cellular and Molecular Medicine (2010), 14 (8), 2151-2161CODEN: JCMMC9; ISSN:1582-1838. (Wiley-Blackwell)The present study identified a novel mechanism of induction of apoptosis in glioblastoma cells by scriptaid - a histone deacetylase (HDAC) inhibitor. Scriptaid reduced glioma cell viability by increasing Jun N-terminal kinase (JNK) activation. Although scriptaid induced activation of both p38MAPK and JNK, it was the inhibition of JNK that attenuated scriptaid-induced apoptosis significantly. Scriptaid also increased the expression of (i) p21 and p27 involved in cell-cycle regulation and (ii) γH2AX assocd. with DNA damage response in a JNK-dependent manner. Treatment with scriptaid increased Ras activity in glioma cells, and transfection of cells with constitutively active RasV12 further sensitized glioma cells to scriptaid-induced apoptosis. Scriptaid also inhibited telomerase activity independent of JNK. Taken together, our findings indicate that scriptaid (i) induces apoptosis and reduces glioma cell proliferation by elevating JNK activation and (ii) also decreases telomerase activity in a JNK-independent manner.
- 70Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.; Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.; Boyapalle, S.; Atadja, P.; Seto, E.; Bhalla, K. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005, 280, 26729– 26734, DOI: 10.1074/jbc.C500186200[Crossref], [PubMed], [CAS], Google Scholar70https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmt1Ggs7w%253D&md5=0d634a576233827dc91d6b3044e56546Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitorsBali, Purva; Pranpat, Michael; Bradner, James; Balasis, Maria; Fiskus, Warren; Guo, Fei; Rocha, Kathy; Kumaraswamy, Sandhya; Boyapalle, Sandhya; Atadja, Peter; Seto, Edward; Bhalla, KapilJournal of Biological Chemistry (2005), 280 (29), 26729-26734CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The hydroxamic acid (HAA) analog pan-histone deacetylase (HDAC) inhibitors (HDIs) LAQ824 and LBH589 have been shown to induce acetylation and inhibit the ATP binding and chaperone function of heat shock protein (HSP) 90. This promotes the polyubiquitylation and degrdn. of the pro-growth and pro-survival client proteins Bcr-Abl, mutant FLT-3, c-Raf, and AKT in human leukemia cells. HDAC6 is a member of the class IIB HDACs. It is predominantly cytosolic, microtubule-assocd. α-tubulin deacetylase that is also known to promote aggresome inclusion of the misfolded polyubiquitylated proteins. Here the authors demonstrate that in the Bcr-abl oncogene expressing human leukemia K562 cells, HDAC6 can be coimmunopptd. with HSP90, and the knock-down of HDAC6 by its siRNA induced the acetylation of HSP90 and α-tubulin. Depletion of HDAC6 levels also inhibited the binding of HSP90 to ATP, reduced the chaperone assocn. of HSP90 with its client proteins, e.g. Bcr-Abl, and induced polyubiquitylation and partial depletion of Bcr-Abl. Conversely, the ectopic overexpression of HDAC6 inhibited LAQ824-induced acetylation of HSP90 and α-tubulin and reduced LAQ824-mediated depletion of Bcr-Abl, AKT, and c-Raf. Collectively, these findings indicate that HDAC6 is also an HSP90 deacetylase. Targeted inhibition of HDAC6 leads to acetylation of HSP90 and disruption of its chaperone function, resulting in polyubiquitylation and depletion of pro-growth and pro-survival HSP90 client proteins including Bcr-Abl. Depletion of HDAC6 sensitized human leukemia cells to HAA-HDIs and proteasome inhibitors.
- 71Kovacs, J. J.; Murphy, P. J.; Gaillard, S.; Zhao, X.; Wu, J. T.; Nicchitta, C. V.; Yoshida, M.; Toft, D. O.; Pratt, W.; Yao, T. P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol. Cell 2005, 18, 601– 607, DOI: 10.1016/j.molcel.2005.04.021[Crossref], [PubMed], [CAS], Google Scholar71https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXltFOksb4%253D&md5=338a8456c56a74d82ad3d28cbccae33fHDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptorKovacs, Jeffrey J.; Murphy, Patrick J. M.; Gaillard, Stephanie; Zhao, Xuan; Wu, June-Tai; Nicchitta, Christopher V.; Yoshida, Minoru; Toft, David O.; Pratt, William B.; Yao, Tso-PangMolecular Cell (2005), 18 (5), 601-607CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)The mol. chaperone heat shock protein 90 (Hsp90) and its accessory cochaperones function by facilitating the structural maturation and complex assembly of client proteins, including steroid hormone receptors and selected kinases. By promoting the activity and stability of these signaling proteins, Hsp90 has emerged as a crit. modulator in cell signaling. Here, we present evidence that Hsp90 chaperone activity is regulated by reversible acetylation and controlled by the deacetylase HDAC6. We show that HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, its dissocn. from an essential cochaperone, p23, and a loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Our results identify Hsp90 as a target of HDAC6 and suggest reversible acetylation as a unique mechanism that regulates Hsp90 chaperone complex activity.
- 72Place, R. F.; Noonan, E. J.; Giardina, C. HDAC inhibition prevents NF-kappa B activation by suppressing proteasome activity: down-regulation of proteasome subunit expression stabilizes I kappa B alpha. Biochem. Pharmacol. 2005, 70, 394– 406, DOI: 10.1016/j.bcp.2005.04.030[Crossref], [PubMed], [CAS], Google Scholar72https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXlvVWms7w%253D&md5=c2bb273b4516e1dcb19e7138022f8256HDAC inhibition prevents NF-κB activation by suppressing proteasome activity: Down-regulation of proteasome subunit expression stabilizes IκBαPlace, Robert F.; Noonan, Emily J.; Giardina, CharlesBiochemical Pharmacology (2005), 70 (3), 394-406CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)The short chain fatty acid (SCFA) butyrate (BA) and other histone deacetylase (HDAC) inhibitors can rapidly induce cell cycle arrest and differentiation of colon cancer cell lines. We found that butyrate and the specific HDAC inhibitor trichostatin A (TSA) can reprogram the NF-κB response in colon cancer cells. Specifically, TNF-α activation is suppressed in butyrate-differentiated cells, whereas IL-1β activation is largely unaffected. To gain insight into the relation between butyrate-induced differentiation and NF-κB regulation, we detd. the impact of butyrate on proteasome activity and subunit expression. Interestingly, butyrate and TSA reduced the cellular proteasome activity in colon cancer cell lines. The drop in proteasome activity results from the reduced expression of the catalytic β-type subunits of the proteasome at both the protein and mRNA level. The selective impact of HDAC inhibitors on TNF-α-induced NF-κB activation appears to relate to the fact that the TNF-α-induced activation of NF-κB is mediated by the proteasome, whereas NF-κB activation by IL-1β is largely proteasome-independent. These findings indicate that cellular differentiation status and/or proliferative capacity can significantly impact proteasome activity and selectively alter NF-κB responses in colon cancer cells. This information may be useful for the further development and targeting of HDAC inhibitors as anti-neoplastic and anti-inflammatory agents.
- 73Fotheringham, S.; Epping, M. T.; Stimson, L.; Khan, O.; Wood, V.; Pezzella, F.; Bernards, R.; La Thangue, N. B. Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosis. Cancer Cell 2009, 15, 57– 66, DOI: 10.1016/j.ccr.2008.12.001[Crossref], [PubMed], [CAS], Google Scholar73https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXptVKjsg%253D%253D&md5=bb971959fe4e67320160eb8e925f8945Genome-wide loss-of-function screen reveals an important role for the proteasome in HDAC inhibitor-induced apoptosisFotheringham, Susan; Epping, Mirjam T.; Stimson, Lindsay; Khan, Omar; Wood, Victoria; Pezzella, Francesco; Bernards, Rene; La Thangue, Nicholas B.Cancer Cell (2009), 15 (1), 57-66CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.
- 74Mishima, Y.; Santo, L.; Eda, H.; Cirstea, D.; Nemani, N.; Yee, A. J.; O’Donnell, E.; Selig, M. K.; Quayle, S. N.; Arastu-Kapur, S.; Kirk, C.; Boise, L. H.; Jones, S. S.; Raje, N. Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death. Br. J. Haematol. 2015, 169, 423– 434, DOI: 10.1111/bjh.13315[Crossref], [PubMed], [CAS], Google Scholar74https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXms1SksLw%253D&md5=3a0757a3514b4db9e3ddb11c6cd0869aRicolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell deathMishima, Yuko; Santo, Loredana; Eda, Homare; Cirstea, Diana; Nemani, Neeharika; Yee, Andrew J.; O'Donnell, Elizabeth; Selig, Martin Karl; Quayle, Steven N.; Arastu-Kapur, Shirin; Kirk, Christopher; Boise, Lawrence H.; Jones, Simon S.; Raje, NoopurBritish Journal of Haematology (2015), 169 (3), 423-434CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We obsd. that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addn. of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumor vol., assocd. with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.
- 75Kawaguchi, Y.; Kovacs, J. J.; McLaurin, A.; Vance, J. M.; Ito, A.; Yao, T. P. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003, 115, 727– 738, DOI: 10.1016/S0092-8674(03)00939-5[Crossref], [PubMed], [CAS], Google Scholar75https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXhtVWgurfL&md5=4bb225e89efa841c73b6ca12284cbb06The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stressKawaguchi, Yoshiharu; Kovacs, Jeffrey J.; McLaurin, Adam; Vance, Jeffery M.; Ito, Akihiro; Yao, Tso-pangCell (Cambridge, MA, United States) (2003), 115 (6), 727-738CODEN: CELLB5; ISSN:0092-8674. (Cell Press)The efficient clearance of cytotoxic misfolded protein aggregates is crit. for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-assocd. deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.
- 76Martínez-Iglesias, O.; Ruiz-Llorente, L.; Sánchez-Martínez, R.; García, L.; Zambrano, A.; Aranda, A. Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clin. Transl. Oncol. 2008, 10, 395– 398, DOI: 10.1007/s12094-008-0221-x[Crossref], [PubMed], [CAS], Google Scholar76https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVGlsr3P&md5=50266183f85aae8eae9d1fd6a0113429Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancerMartinez-Iglesias, Olaia; Ruiz-Llorente, Lidia; Sanchez-Martinez, Ruth; Garcia, Laura; Zambrano, Alberto; Aranda, AnaClinical & Translational Oncology (2008), 10 (7), 395-398CODEN: CTOLAM; ISSN:1699-048X. (Springer)A review. Histone deacetylases (HDACs) remove the acetyl groups of lysine residues of histone tails leading to chromatin compaction and transcriptional repression. In addn., HDACs can also influence transcription-independent events such as mitosis or DNA (DNA) repair and deacetylate nonhistone proteins involved in cell proliferation and death, altering their function. Histone deacetylase inhibitors (HDACi) constitute a promising treatment for cancer therapy due to their low toxicity. HDACi have been shown to induce differentiation, cell-cycle arrest, and apoptosis and to inhibit migration, invasion, and angiogenesis in many cancer cell lines. In addn., these compds. inhibit tumor growth in animal models and show antitumor activity in patients. HDACi alone and in combination with a variety of anticancer drugs are being tested in clin. trials, showing significant anticancer activity both in hematol. and solid tumors. SAHA (vorinostat, Zolinza) was the first HDACi approved by the US Food and Drug Administration to enter the clin. oncol. market for treating cutaneous T-cell lymphoma (CTCL) and is being tested for other malignancies.
- 77Thaler, F. Current trends in the development of histone deacetylase inhibitors: a review of recent patent applications. Pharm. Pat. Anal. 2012, 1, 75– 90, DOI: 10.4155/ppa.11.3[Crossref], [PubMed], [CAS], Google Scholar77https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmvVaru7c%253D&md5=15fc09940fb573d7461f15b11ca9c2b2Current trends in the development of histone deacetylase inhibitors: a review of recent patent applicationsThaler, FlorianPharmaceutical Patent Analyst (2012), 1 (1), 75-90CODEN: PPAHCN; ISSN:2046-8954. (Future Science Ltd.)A review. Histone deacetylases (HDACs) have become an important target for the treatment of cancer and other diseases. Currently, more than ten HDAC inhibitors have entered clin. studies and two of them have already reached the market. The hydroxamic acid deriv. SAHA (also known as vorinostat or Zolinza) and the cyclic depsipeptide FK228 (romidepsin or Istodax) have gained approval from the US FDA for the treatment of cutaneous T-cell lymphoma. Nevertheless, there has been a continuous effort aimed at discovering a new generation of clin. candidates with improved pharmaceutical properties. This review provides a summary of the most recent patents published from mid-2009 to mid-2011.
- 79Reimer, P. New developments in the treatment of peripheral T-cell lymphoma - role of belinostat. Cancer Manage. Res. 2015, 7, 145– 151, DOI: 10.2147/CMAR.S85351[Crossref], [PubMed], [CAS], Google Scholar79https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2MbksVSlsw%253D%253D&md5=fb2ce8a29f5403657fa702baca9ef283New developments in the treatment of peripheral T-cell lymphoma - role of BelinostatReimer PeterCancer management and research (2015), 7 (), 145-51 ISSN:1179-1322.Peripheral T-cell lymphomas (PTCL) represent a heterogeneous group of rare malignancies that with the exception of anaplastic lymphoma kinase expressing anaplastic large cell lymphoma, share a poor outcome after standard (eg, anthracycline-based) chemotherapy. Most patients are either refractory to initial therapy or eventually relapse. Randomized studies for relapsed/refractory PTCL are not available, however, recently published data show that conventional chemotherapy has very limited efficacy in the salvage setting. Thus, novel drugs are urgently needed to improve the outcome in this setting. Belinostat, a pan-histone deacetylase inhibitor, has demonstrated meaningful efficacy and a favorable toxicity profile in two single-arm Phase II trials on 153 patients with relapsed/refractory PTCL. The conclusive results led to an accelerated approval by the US Food and Drug Administration. The present review summarizes the clinical data available for belinostat, its current role, and future perspectives.
- 80Lee, H. Z.; Kwitkowski, V. E.; Del Valle, P. L.; Ricci, M. S.; Saber, H.; Habtemariam, B. A.; Bullock, J.; Bloomquist, E.; Li Shen, Y.; Chen, X. H.; Brown, J.; Mehrotra, N.; Dorff, S.; Charlab, R.; Kane, R. C.; Kaminskas, E.; Justice, R.; Farrell, A. T.; Pazdur, R. FDA approval: belinostat for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. Clin. Cancer Res. 2015, 21, 2666– 2670, DOI: 10.1158/1078-0432.CCR-14-3119[Crossref], [PubMed], [CAS], Google Scholar80https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVajurfM&md5=c1e64c9d01d18272d25ad03001e7041aFDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell LymphomaLee, Hyon-Zu; Kwitkowski, Virginia E.; Del Valle, Pedro L.; Ricci, M. Stacey; Saber, Haleh; Habtemariam, Bahru A.; Bullock, Julie; Bloomquist, Erik; Shen, Yuan Li; Chen, Xiao-Hong; Brown, Janice; Mehrotra, Nitin; Dorff, Sarah; Charlab, Rosane; Kane, Robert C.; Kaminskas, Edvardas; Justice, Robert; Farrell, Ann T.; Pazdur, RichardClinical Cancer Research (2015), 21 (12), 2666-2670CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered i.v. at a dose of 1000 mg/m2 over 30 min once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiol. readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathol. Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), resp. The median duration of response, the key secondary efficacy endpoint, was 8.4 mo (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL. Clin Cancer Res; 21(12); 2666-70. ©2015 AACR.
- 81Poole, R. M. Belinostat: first global approval. Drugs 2014, 74, 1543– 1554, DOI: 10.1007/s40265-014-0275-8[Crossref], [PubMed], [CAS], Google Scholar81https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtl2nsrzL&md5=b8bc6efe62e7fd78d6a9d022a8d96559Belinostat: First Global ApprovalPoole, Raewyn M.Drugs (2014), 74 (13), 1543-1554CODEN: DRUGAY; ISSN:0012-6667. (Springer International Publishing AG)A review. Belinostat [Beleodaq (US)], a small-mol. hydroxamate-type inhibitor of class I, II and IV histone deacetylase (HDAC) enzymes, has been developed by TopoTarget and Spectrum Pharmaceuticals for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat has received its first global approval as monotherapy for this indication in the US, under the Food and Drug Administration's accelerated approval program. This article summarizes the milestones in the development of belinostat leading to this first approval for the treatment of PTCL.
- 82Tandon, N.; Ramakrishnan, V.; Kumar, S. K. Clinical use and applications of histone deacetylase inhibitors in multiple myeloma. Clin. Pharmacol.: Adv. Appl. 2016, 8, 35– 44, DOI: 10.2147/CPAA.S94021[Crossref], [PubMed], [CAS], Google Scholar82https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXmtlertro%253D&md5=c5ad697e90297b2a2397737098dde73cClinical use and applications of histone deacetylase inhibitors in multiple myelomaTandon, Nidhi; Ramakrishnan, Vijay; Kumar, Shaji K.Clinical Pharmacology: Advances and Applications (2016), 8 (), 35-44CODEN: CPAAGX; ISSN:1179-1438. (Dove Medical Press Ltd.)The incorporation of various novel therapies has resulted in a significant survival benefit in newly diagnosed and relapsed patients with multiple myeloma (MM) over the past decade. Despite these advances, resistance to therapy leads to eventual relapse and fatal outcomes in the vast majority of patients. Hence, there is an unmet need for new safe and efficacious therapies for continued improvement in outcomes. Given the role of epigenetic aberrations in the pathogenesis and progression of MM and the success of histone deacetylase inhibitors (HDACi) in other malignancies, many HDACi have been tried in MM. Various preclin. studies helped us to understand the antimyeloma activity of different HDACi in MM as a single agent or in combination with conventional, novel, and immune therapies. The early clin. trials of HDACi depicted only modest single-agent activity, but recent studies have revealed encouraging clin. response rates in combination with other antimyeloma agents, esp. proteasome inhibitors. This led to the approval of the combination of panobinostat and bortezomib for the treatment of relapsed/refractory MM patients with two prior lines of treatment by the US Food and Drug Administration. However, it remains yet to be defined how we can incorporate HDACi in the current therapeutic paradigms for MM that will help to achieve longer disease control and significant survival benefits. In addn., isoform-selective and/or class-selective HDAC inhibition to reduce unfavorable side effects needs further evaluation.
- 83Ribrag, V.; Kim, V. S.; Bouabdallah, R.; Lim, S. T.; Coiffier, B.; Illes, A.; Lemieux, B.; Dyer, M. J. S.; Offner, F.; Felloussi, Z.; Kloos, I.; Luan, Y.; Vezan, R.; Graef, T.; Morschhauser, F. Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II study. Haematologica 2017, 102, 903– 909, DOI: 10.3324/haematol.2016.154377[Crossref], [PubMed], [CAS], Google Scholar83https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitVWlurnP&md5=4368682e077c9e36057685cb45103276Safety and efficacy of abexinostat, a pan-histone deacetylase inhibitor, in non-Hodgkin lymphoma and chronic lymphocytic leukemia: results of a phase II studyRibrag, Vincent; Kim, Won Seog; Bouabdallah, Reda; Lim, Soon Thye; Coiffier, Bertrand; Illes, Arpad; Lemieux, Bernard; Dyer, Martin J. S.; Offner, Fritz; Felloussi, Zakia; Kloos, Ioana; Luan, Ying; Vezan, Remus; Graef, Thorsten; Morschhauser, FranckHaematologica (2017), 102 (5), 903-909CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)Histone deacetylase inhibitors are members of a class of epigenetic drugs that have proven activity in T-cell malignancies, but little is known about their efficacy in B-cell lymphomas. Abexinostat is an orally available hydroxamate-contg. histone deacetylase inhibitor that differs from approved inhibitors; its unique pharmacokinetic profile and oral dosing schedule, twice daily four hours apart, allows for continuous exposure at concns. required to efficiently kill tumor cells. In this phase II study, patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia received oral abexinostat at 80 mg BID for 14 days of a 21-day cycle and continued until progressive disease or unacceptable toxicity. A total of 100 patients with B-cell malignancies and T-cell lymphomas were enrolled between Oct. 2011 and July 2014. All patients received at least one dose of study drug. Primary reasons for discontinuation included progressive disease (56%) and adverse events (25%). Grade 3 or over adverse events and any serious adverse events were reported in 88% and 73% of patients, resp. The most frequently reported grade 3 or over treatment-emergent related adverse events were thrombocytopenia (80%), neutropenia (27%), and anemia (12%). Among the 87 patients evaluable for efficacy, overall response rate was 28% (complete response 5%), with highest responses obsd. in patients with follicular lymphoma (overall response rate 56%), T-cell lymphoma (overall response rate 40%), and diffuse large Bcell lymphoma (overall response rate 31%). Further investigation of the safety and efficacy of abexinostat in follicular lymphoma, T-cell lymphoma, and diffuse large B-cell lymphoma implementing a less doseintense week-on-week-off schedule is warranted.
- 84Tak, W. Y.; Ryoo, B. Y.; Lim, H. Y.; Kim, D. Y.; Okusaka, T.; Ikeda, M.; Hidaka, H.; Yeon, J. E.; Mizukoshi, E.; Morimoto, M.; Lee, M. A.; Yasui, K.; Kawaguchi, Y.; Heo, J.; Morita, S.; Kim, T. Y.; Furuse, J.; Katayama, K.; Aramaki, T.; Hara, R.; Kimura, T.; Nakamura, O.; Kudo, M. Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patients. Invest. New Drugs 2018, 36, 1072– 1084, DOI: 10.1007/s10637-018-0658-x[Crossref], [PubMed], [CAS], Google Scholar84https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs12it7bI&md5=76f6a72614eebfad7cb38e63f0db8f62Phase I/II study of first-line combination therapy with sorafenib plus resminostat, an oral HDAC inhibitor, versus sorafenib monotherapy for advanced hepatocellular carcinoma in east Asian patientsTak, Won Young; Ryoo, Baek-Yeol; Lim, Ho Yeong; Kim, Do-Young; Okusaka, Takuji; Ikeda, Masafumi; Hidaka, Hisashi; Yeon, Jong-Eun; Mizukoshi, Eishiro; Morimoto, Manabu; Lee, Myung-Ah; Yasui, Kohichiroh; Kawaguchi, Yasunori; Heo, Jeong; Morita, Sojiro; Kim, Tae-You; Furuse, Junji; Katayama, Kazuhiro; Aramaki, Takeshi; Hara, Rina; Kimura, Takuya; Nakamura, Osamu; Kudo, MasatoshiInvestigational New Drugs (2018), 36 (6), 1072-1084CODEN: INNDDK; ISSN:0167-6997. (Springer)Resminostat is an oral inhibitor of class I, IIB, and IV histone deacetylases. This phase I/II study compared the safety and efficacy of resminostat plus sorafenib vs. sorafenib monotherapy as first-line therapy for advanced hepatocellular carcinoma (HCC). In phase I, resminostat (400 mg or 600 mg/day on days 1 to 5 every 14 days) was administered with sorafenib (800 mg/day for 14 days) to det. the recommended dose for phase II. In phase II, patients were randomized (1:1) to sorafenib monotherapy or resminostat plus sorafenib. The primary endpoint was time-to-progression (TTP). Nine patients (3: 400 mg, 6: 600 mg) were enrolled in phase I, and the recommended dose of resminostat was detd. to be 400 mg/day. Then 170 patients were enrolled in phase II. Median TTP/overall survival (OS) were 2.8/14.1 mo with monotherapy vs. 2.8/11.8 mo with combination therapy (Hazard Ratio [HR]: 0.984, p = 0.925/HR: 1.046, p = 0.824). The overall incidence of adverse events was similar in both groups (98.8% vs. 100.0%). However, thrombocytopenia ≥ Grade 3 was significantly more frequent in the combination therapy group (34.5% vs. 2.4%, p < 0.001). Subgroup anal. revealed that median TTP/OS was 1.5/6.9 mo for monotherapy vs. 2.8/13.1 mo for combination therapy (HR: 0.795, p = 0.392/HR: 0.567, p = 0.065) among patients with a normal-to-high baseline platelet count (≥ 150 × 103/mm3). In patients with advanced HCC, first-line therapy with resminostat at the recommended dose plus sorafenib showed no significant efficacy advantage over sorafenib monotherapy.
- 85Galli, M.; Salmoiraghi, S.; Golay, J.; Gozzini, A.; Crippa, C.; Pescosta, N.; Rambaldi, A. A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myeloma. Ann. Hematol. 2010, 89, 185– 190, DOI: 10.1007/s00277-009-0793-8[Crossref], [PubMed], [CAS], Google Scholar85https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXjt1yltw%253D%253D&md5=0aa6301364211146a0dcb8d97fd38aa8A phase II multiple dose clinical trial of histone deacetylase inhibitor ITF2357 in patients with relapsed or progressive multiple myelomaGalli, Monica; Salmoiraghi, Silvia; Golay, Josee; Gozzini, Antonella; Crippa, Claudia; Pescosta, Norbert; Rambaldi, AlessandroAnnals of Hematology (2010), 89 (2), 185-190CODEN: ANHEE8; ISSN:0939-5555. (Springer)ITF2357, an orally effective member of the family of histone deacetylase inhibitors, is a potent inducer of apoptosis and death of multiple myeloma (MM) cells. We performed a phase-II, multiple-dose clin. trial in 19 patients with relapsed or progressive MM to det. the max. tolerated dose (MTD) of ITF2357 administered twice daily for four consecutive days every week for 4 wk (i.e., first cycle). The first six patients received 150 mg ITF2357 twice daily. Since two of them experienced a dose-limiting toxicity (DLT) during the first cycle, the subsequent patients received 100 mg ITF2357 twice daily. This was the MTD, as only one DLT occurred. Up to 12 wk (i.e., three cycles) of treatment were scheduled. Oral dexamethasone was allowed to a max. weekly amt. of 20 mg. Median duration of treatment was 6 wk, ranging from two (two patients) to 12 wk (five patients). Four patients suffered from serious adverse events. Three patients experienced grade 3-4 gastro-intestinal toxicity and three had transient electrocardiog. abnormalities. Thrombocytopenia occurred in all but one patient (grade 3-4 in ten patients). At last follow-up, five patients were in stable disease, five had disease progression, and nine had died all of progressive MM. In conclusion, when given at a dose of 100 mg twice daily alone or combined with dexamethasone, ITF2357 proved tolerable but showed a modest clin. benefit in advanced MM.
- 86Finazzi, G.; Vannucchi, A. M.; Martinelli, V.; Ruggeri, M.; Nobile, F.; Specchia, G.; Pogliani, E. M.; Olimpieri, O. M.; Fioritoni, G.; Musolino, C.; Cilloni, D.; Sivera, P.; Barosi, G.; Finazzi, M. C.; Di Tollo, S.; Demuth, T.; Barbui, T.; Rambaldi, A. A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br. J. Haematol. 2013, 161, 688– 694, DOI: 10.1111/bjh.12332[Crossref], [PubMed], [CAS], Google Scholar86https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXnvVGisrY%253D&md5=ec3a1a0cd05344cb0975818d459f04d6A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapyFinazzi, Guido; Vannucchi, Alessandro M.; Martinelli, Vincenzo; Ruggeri, Marco; Nobile, Francesco; Specchia, Giorgina; Pogliani, Enrico Maria; Olimpieri, Odoardo Maria; Fioritoni, Giuseppe; Musolino, Caterina; Cilloni, Daniela; Sivera, Piera; Barosi, Giovanni; Finazzi, Maria Chiara; Di Tollo, Silvia; Demuth, Tim; Barbui, Tiziano; Rambaldi, AlessandroBritish Journal of Haematology (2013), 161 (5), 688-694CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Givinostat, a histone-deacetylase inhibitor (HDACi), inhibits proliferation of cells bearing the JAK2 V617F mutation and has shown significant activity with good tolerability in patients with chronic myeloproliferative neoplasms (MPN). In this multicentre, open-label, phase II study, 44 patients with polycythemia vera (PV), unresponsive to the max. tolerated doses (MTD) of hydroxycarbamide (HC), were treated with Givinostat (50 or 100 mg/d) in combination with MTD of HC. The European LeukemiaNet response criteria were used to assess the primary endpoint after 12 wk of treatment. Complete or partial response was obsd. in 55% and 50% of patients receiving 50 or 100 mg of Givinostat, resp. Control of pruritus was obsd. in 64% and 67% of patients in the 50 and 100 mg groups, resp. The combination of Givinostat and HC was well tolerated: eight patients (18%) discontinued, four in each treatment arm; grade 3 adverse events were reported in one patient (4·5%) in each treatment arm. The combined use of Givinostat and HC was safe and clin. effective in HC-unresponsive PV patients.
- 87Garcia-Manero, G.; Abaza, Y.; Takahashi, K.; Medeiros, B. C.; Arellano, M.; Khaled, S. K.; Patnaik, M.; Odenike, O.; Sayar, H.; Tummala, M.; Patel, P.; Maness-Harris, L.; Stuart, R.; Traer, E.; Karamlou, K.; Yacoub, A.; Ghalie, R.; Giorgino, R.; Atallah, E. Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study. Blood Adv. 2019, 3, 508– 518, DOI: 10.1182/bloodadvances.2018027409[Crossref], [PubMed], [CAS], Google Scholar87https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslyht7%252FL&md5=4a1a8b98ee7ef7f39ea5e445feb7aa75Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 studyGarcia-Manero, Guillermo; Abaza, Yasmin; Takahashi, Koichi; Medeiros, Bruno C.; Arellano, Martha; Khaled, Samer K.; Patnaik, Mrinal; Odenike, Olatoyosi; Sayar, Hamid; Tummala, Mohan; Patel, Prapti; Maness-Harris, Lori; Stuart, Robert; Traer, Elie; Karamlou, Kasra; Yacoub, Abdulraheem; Ghalie, Richard; Giorgino, Ruben; Atallah, EhabBlood Advances (2019), 3 (4), 508-518CODEN: BALDBA; ISSN:2473-9537. (American Society of Hematology)Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for std. induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphol. leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapyrelated AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 mo (95% confidence interval [CI], 10-26.5 mo) and 12.6 mo (95% CI, 10-17.7 mo), resp., with a 1-yr OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, resp. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing.
- 88Yalniz, F. F.; Berdeja, J. G.; Maris, M. B.; Lyons, R. M.; Reeves, J. A., Jr; Essell, J. H.; Patel, P.; Sekeres, M.; Hughes, A.; Mappa, S.; Garcia-Manero, G. A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapy. Br. J. Haematol. 2020, 188, 404– 412, DOI: 10.1111/bjh.16173[Crossref], [PubMed], [CAS], Google Scholar88https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFOiurk%253D&md5=8e4a85ae70a75b02725bf5cc0d9ea104A phase II study of addition of pracinostat to a hypomethylating agent in patients with myelodysplastic syndromes who have not responded to previous hypomethylating agent therapyYalniz, Fevzi F.; Berdeja, Jesus G.; Maris, Michael B.; Lyons, Roger M.; Reeves, James A., Jr.; Essell, James H.; Patel, Prapti; Sekeres, Mikkael; Hughes, Amanda; Mappa, Silvia; Garcia-Manero, GuillermoBritish Journal of Haematology (2020), 188 (3), 404-412CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary : Hypomethylating agents (HMAs) are std. of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to est. the clin. improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematol. improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 mo for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
- 89Chu, Q. S.; Nielsen, T. O.; Alcindor, T.; Gupta, A.; Endo, M.; Goytain, A.; Xu, H.; Verma, S.; Tozer, R.; Knowling, M.; Bramwell, V. B.; Powers, J.; Seymour, L. K.; Eisenhauer, E. A. A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200. Ann. Oncol. 2015, 26, 973– 981, DOI: 10.1093/annonc/mdv033[Crossref], [PubMed], [CAS], Google Scholar89https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2Mrgs1GlsA%253D%253D&md5=911f2bcea1fdcede9dbbcbef8c8e9b21A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†Chu Q S-C; Nielsen T O; Goytain A; Knowling M; Alcindor T; Gupta A; Endo M; Xu H; Powers J; Seymour L K; Eisenhauer E A; Verma S; Tozer R; Bramwell V BAnnals of oncology : official journal of the European Society for Medical Oncology (2015), 26 (5), 973-981 ISSN:.BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.
- 90Child, F.; Ortiz-Romero, P. L.; Alvarez, R.; Bagot, M.; Stadler, R.; Weichenthal, M.; Alves, R.; Quaglino, P.; Beylot-Barry, M.; Cowan, R.; Geskin, L. J.; Pérez-Ferriols, A.; Hellemans, P.; Elsayed, Y.; Phelps, C.; Forslund, A.; Kamida, M.; Zinzani, P. L. Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome. Br. J. Dermatol. 2016, 175, 80– 88, DOI: 10.1111/bjd.14427[Crossref], [PubMed], [CAS], Google Scholar90https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xht1KktbvM&md5=0b64887cee81c36b3667927b3a724ba2Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sezary syndromeChild, F.; Ortiz-Romero, P. L.; Alvarez, R.; Bagot, M.; Stadler, R.; Weichenthal, M.; Alves, R.; Quaglino, P.; Beylot-Barry, M.; Cowan, R.; Geskin, L. J.; Perez-Ferriols, A.; Hellemans, P.; Elsayed, Y.; Phelps, C.; Forslund, A.; Kamida, M.; Zinzani, P. L.British Journal of Dermatology (2016), 175 (1), 80-88CODEN: BJDEAZ; ISSN:0007-0963. (Wiley-Blackwell)Summary : Background : Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. Objectives : To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). Methods : Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. Results : Eight of 26 (25 evaluable) patients achieved ≥ 50% redn. in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 mo. Median PFS was 5·1 mo. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumor biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clin. cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalemia and pyrexia. Conclusions : Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.
- 91Moreau, P.; Facon, T.; Touzeau, C.; Benboubker, L.; Delain, M.; Badamo-Dotzis, J.; Phelps, C.; Doty, C.; Smit, H.; Fourneau, N.; Forslund, A.; Hellemans, P.; Leleu, X. Quisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myeloma. Leuk. Lymphoma 2016, 57, 1546– 1559, DOI: 10.3109/10428194.2015.1117611[Crossref], [PubMed], [CAS], Google Scholar91https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtlSitL0%253D&md5=6161989b835b6ebc93b591ed714ed76fQuisinostat, bortezomib, and dexamethasone combination therapy for relapsed multiple myelomaMoreau, Philippe; Facon, Thierry; Touzeau, Cyrille; Benboubker, Lotfi; Delain, Martine; Badamo-Dotzis, Julie; Phelps, Charles; Doty, Christopher; Smit, Hans; Fourneau, Nele; Forslund, Ann; Hellemans, Peter; Leleu, XavierLeukemia & Lymphoma (2016), 57 (7), 1546-1559CODEN: LELYEA; ISSN:1029-2403. (Taylor & Francis Ltd.)The max. tolerated dose (MTD) of quisinostat + bortezomib + dexamethasone in patients with relapsed multiple myeloma was evaluated in a phase-1b, open-label, multicenter, '3 + 3' dose-escalation study. Patients received escalating doses of oral quisinostat (6 mg [n = 3], 8 mg [n = 3], 10 mg [n = 6], and 12 mg [n = 6] on days 1, 3, and 5/wk) plus s.c. bortezomib (1.3 mg/m2) and oral dexamethasone (20 mg) in cycles of 21 (cycles 1-8) or 35 d (cycles 9-11) until MTD was detd. No dose-limiting toxicities were reported in 6/8 mg groups except ventricular fibrillation (Grade 4 cardiac arrest, n = 1 [10 mg] cycle 6) and clin. significant cardiac toxicities (Grade 3 QTc prolongation, Grade 3 atrial fibrillation, n = 2 [12 mg]). Thrombocytopenia (n = 11), asthenia (n = 10), and diarrhea (n = 12) were most common adverse events. Overall, 88.2% patients achieved treatment response, median duration of response, and median progression-free survival were 9.4 and 8.2 mo, resp. The MTD of quisinostat was established as 10 mg thrice weekly oral dose with bortezomib + dexamethasone.
- 92Venugopal, B.; Baird, R.; Kristeleit, R. S.; Plummer, R.; Cowan, R.; Stewart, A.; Fourneau, N.; Hellemans, P.; Elsayed, Y.; McClue, S.; Smit, J. W.; Forslund, A.; Phelps, C.; Camm, J.; Evans, T. R.; de Bono, J. S.; Banerji, U. A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. Clin. Cancer Res. 2013, 19, 4262– 4272, DOI: 10.1158/1078-0432.CCR-13-0312[Crossref], [PubMed], [CAS], Google Scholar92https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1amt7zP&md5=f4db895a7878fddce61ea9640e427d4dA Phase I Study of Quisinostat (JNJ-26481585), an Oral Hydroxamate Histone Deacetylase Inhibitor with Evidence of Target Modulation and Antitumor Activity, in Patients with Advanced Solid TumorsVenugopal, Balaji; Baird, Richard; Kristeleit, Rebecca S.; Plummer, Ruth; Cowan, Richard; Stewart, Adam; Fourneau, Nele; Hellemans, Peter; Elsayed, Yusri; McClue, Steve; Smit, Johan W.; Forslund, Ann; Phelps, Charles; Camm, John; Evans, T. R. Jeffry; de Bono, Johann S.; Banerji, UdaiClinical Cancer Research (2013), 19 (15), 4262-4272CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: To det. the max.-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi). Exptl. Design: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two-stage accelerated titrn. design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clin. efficacy were evaluated at each schedule. Results: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs obsd. were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The max. plasma concn. (Cmax) and area under the plasma concn.-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 mo). Conclusions: The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule. Clin Cancer Res; 19(15); 4262-72. ©2013 AACR.
- 93Yee, A. J.; Bensinger, W. I.; Supko, J. G.; Voorhees, P. M.; Berdeja, J. G.; Richardson, P. G.; Libby, E. N.; Wallace, E. E.; Birrer, N. E.; Burke, J. N.; Tamang, D. L.; Yang, M.; Jones, S. S.; Wheeler, C. A.; Markelewicz, R. J.; Raje, N. S. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial. Lancet Oncol. 2016, 17, 1569– 1578, DOI: 10.1016/S1470-2045(16)30375-8[Crossref], [PubMed], [CAS], Google Scholar93https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhsl2isb7J&md5=59fea63c11b7bce7be6bd74f195af04bRicolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trialYee, Andrew J.; Bensinger, William I.; Supko, Jeffrey G.; Voorhees, Peter M.; Berdeja, Jesus G.; Richardson, Paul G.; Libby, Edward N.; Wallace, Ellen E.; Birrer, Nicole E.; Burke, Jill N.; Tamang, David L.; Yang, Min; Jones, Simon S.; Wheeler, Catherine A.; Markelewicz, Robert J.; Raje, Noopur S.Lancet Oncology (2016), 17 (11), 1569-1578CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor with reduced class I HDAC activity to be studied clin. Motivated by findings from preclin. studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. In this multicenter phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centers in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 wk of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40-240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a std. 3 + 3 design according to three different regimens on days 1-21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg [in one cohort] to 25 mg [in all other cohorts] once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the max. tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumor activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov, no. NCT01583283. Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We obsd. two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A max. tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1-21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1-2 in 14 [37%] patients; grade 3 in seven [18%]) and diarrhea (grade 1-2 in 15 [39%] patients; grade 3 in two [5%]). Our pharmacodynamic studies showed that at clin. relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumor activity, 21 (55% [95% CI 38-71]) of 38 patients had an overall response. The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma.Acetylon Pharmaceuticals.
- 94Vogl, D. T.; Raje, N.; Jagannath, S.; Richardson, P.; Hari, P.; Orlowski, R.; Supko, J. G.; Tamang, D.; Yang, M.; Jones, S. S.; Wheeler, C.; Markelewicz, R. J.; Lonial, S. Ricolinostat, the first selective histone deacetylase 6 inhibitor, in combination with bortezomib and dexamethasone for relapsed or refractory multiple myeloma. Clin. Cancer Res. 2017, 23, 3307– 3315, DOI: 10.1158/1078-0432.CCR-16-2526[Crossref], [PubMed], [CAS], Google Scholar94https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtFSnurbL&md5=2dd174501d2f331aeb0eff42072001d1Ricolinostat, the First Selective Histone Deacetylase 6 Inhibitor, in Combination with Bortezomib and Dexamethasone for Relapsed or Refractory Multiple MyelomaVogl, Dan T.; Raje, Noopur; Jagannath, Sundar; Richardson, Paul; Hari, Parameswaran; Orlowski, Robert; Supko, Jeffrey G.; Tamang, David; Yang, Min; Jones, Simon S.; Wheeler, Catherine; Markelewicz, Robert J.; Lonial, SagarClinical Cancer Research (2017), 23 (13), 3307-3315CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclin. models suggest that the obsd. synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degrdn. Exptl. Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with std. proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle. Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clin. responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematol., gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes. Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.
- 95Gao, X.; Shen, L.; Li, X.; Liu, J. Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta-analysis of clinical trials. Exp. Ther. Med. 2019, 18, 1057– 1068, DOI: 10.3892/etm.2019.7704[Crossref], [PubMed], [CAS], Google Scholar95https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvFOlu7fF&md5=76b38fadb3a41671d1ac93635c8b3cf7Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta-analysis of clinical trialsGao, Xiao; Shen, Lijing; Li, Xiang; Liu, JiayingExperimental and Therapeutic Medicine (2019), 18 (2), 1057-1068CODEN: ETMXA2; ISSN:1792-1015. (Spandidos Publications Ltd.)A review. Multiple myeloma (MM) remains incurable primarily due to relapse. Histone deacetylase inhibitors (HDACis) have shown potential application for the treatment of relapsed/refractory multiple myeloma (RRMM). To assess the efficacy and safety of HDACis in RRMM treatment, a systematic review and meta-anal. were conducted based on clin. trial data. A literature search was performed using PubMed, EMBASE, Web of Science and the Cochrane Library databases. Subsequently, 19 trials with 2193 patients treated with one of the three HDACis, panobinostat, ricolinostat and vorinostat, were identified and included in the present study. The efficacy and toxicity of each agent were assessed. The data were pooled using a random effects model in STATA 13.0. The results showed that the overall response rate (ORR) was 0.64 with a 95% confidence interval (CI) of 0.61-0.68 for panobinostat, 0.51 (95% CI, 0.46-0.55) for vorinostat and 0.38 (95% CI, 0.29-0.48) for ricolinostat. Addnl., subgroup anal. revealed an ORR of 0.36 (95% CI, 0.27-0.46) for HDACis-treated bortezomib-refractory MM patients and 0.43 (95% CI, 0.30-0.55) for lenalidomide-refractory patients. The most common grade 3 and 4 hematol. adverse events were thrombocytopenia, neutropenia and anemia. Non-hematol. adverse events included fatigue/asthenia, diarrhea and nausea. In conclusion, anal. of the pooled data revealed that panobinostat-contg. regimens were effective and tolerable for patients with RRMM. Furthermore, lenalidomide-refractory patients may derive greater benefits from these regimens. More clin. and real-world studies are required to validate these results.
- 96Shimizu, T.; LoRusso, P. M.; Papadopoulos, K. P.; Patnaik, A.; Beeram, M.; Smith, L. S.; Rasco, D. W.; Mays, T. A.; Chambers, G.; Ma, A.; Wang, J.; Laliberte, R.; Voi, M.; Tolcher, A. W. Phase I first-in-human study of CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 in patients with advanced solid tumors. Clin. Cancer Res. 2014, 20, 5032– 5040, DOI: 10.1158/1078-0432.CCR-14-0570[Crossref], [PubMed], [CAS], Google Scholar96https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs12gtbzP&md5=62860afa08733980f47047880e11a5baPhase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid TumorsShimizu, Toshio; LoRusso, Patricia M.; Papadopoulos, Kyri P.; Patnaik, Amita; Beeram, Muralidhar; Smith, Lon S.; Rasco, Drew W.; Mays, Theresa A.; Chambers, Glenda; Ma, Anna; Wang, Jing; Laliberte, Robert; Voi, Maurizio; Tolcher, Anthony W.Clinical Cancer Research (2014), 20 (19), 5032-5040CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-h i.v. (i.v.) infusion for 5 consecutive days every 2 wk. Exptl. Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75-300 mg/m2/day) following a std. 3 + 3 dose escalation design. Results: The MTD was detd. to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean max. concn. (Cmax), clearance (CL), vol. of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 h, resp. Acetylated histone H3 induction was obsd. in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. Conclusion: CUDC-101 administered by 1-h i.v. infusion for 5 consecutive days every 2 wk was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clin. testing. Clin Cancer Res; 20(19); 5032-40. ©2014 AACR.
- 97Galloway, T. J.; Wirth, L. J.; Colevas, A. D.; Gilbert, J.; Bauman, J. E.; Saba, N. F.; Raben, D.; Mehra, R.; Ma, A. W.; Atoyan, R.; Wang, J.; Burtness, B.; Jimeno, A. A phase I study of CUDC-101, a multitarget inhibitor of hdacs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma. Clin. Cancer Res. 2015, 21, 1566– 1573, DOI: 10.1158/1078-0432.CCR-14-2820[Crossref], [PubMed], [CAS], Google Scholar97https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXmtVahs7o%253D&md5=dd6b5663ffbf995b5def843a8b8b7556A Phase I Study of CUDC-101, a Multitarget Inhibitor of HDACs, EGFR, and HER2, in Combination with Chemoradiation in Patients with Head and Neck Squamous Cell CarcinomaGalloway, Thomas J.; Wirth, Lori J.; Colevas, Alexander D.; Gilbert, Jill; Bauman, Julie E.; Saba, Nabil F.; Raben, David; Mehra, Ranee; Ma, Anna W.; Atoyan, Ruzanna; Wang, Jing; Burtness, Barbara; Jimeno, AntonioClinical Cancer Research (2015), 21 (7), 1566-1573CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)CUDC-101 is a small mol. that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclin. activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to det. the max. tolerated dose (MTD) of CUDC-101 with cisplatin-radiotherapy in the treatment of HNSCC. CUDC-101 monotherapy was administered i.v. three times weekly (Monday, Wednesday, Friday) for a one-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 wk) and external beam radiation (70 Gy to gross disease) over 7 wk. Twelve patients with intermediate or high-risk HNSCC enrolled. Eleven were p16INKa (p16)-neg. The MTD of CUDC-101-based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose-limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMC), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining nine patients are free of progression. CUDC-101, cisplatin, and radiation were feasible in intermediate-/high-risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration. Clin Cancer Res; 21(7); 1566-73. ©2015 AACR.
- 98Shi, Y.; Jia, B.; Xu, W.; Li, W.; Liu, T.; Liu, P.; Zhao, W.; Zhang, H.; Sun, X.; Yang, H.; Zhang, X.; Jin, J.; Jin, Z.; Li, Z.; Qiu, L.; Dong, M.; Huang, X.; Luo, Y.; Wang, X.; Wang, X.; Wu, J.; Xu, J.; Yi, P.; Zhou, J.; He, H.; Liu, L.; Shen, J.; Tang, X.; Wang, J.; Yang, J.; Zeng, Q.; Zhang, Z.; Cai, Z.; Chen, X.; Ding, K.; Hou, M.; Huang, H.; Li, X.; Liang, R.; Liu, Q.; Song, Y.; Su, H.; Gao, Y.; Liu, L.; Luo, J.; Su, L.; Sun, Z.; Tan, H.; Wang, H.; Wang, J.; Wang, S.; Zhang, H.; Zhang, X.; Zhou, D.; Bai, O.; Wu, G.; Zhang, L.; Zhang, Y. Chidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in China. J. Hematol. Oncol. 2017, 10, 69, DOI: 10.1186/s13045-017-0439-6[Crossref], [PubMed], [CAS], Google Scholar98https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXksl2htrk%253D&md5=6b3172600b76e6025fc5569446f6362dChidamide in relapsed or refractory peripheral T cell lymphoma: a multicenter real-world study in ChinaShi, Yuankai; Jia, Bo; Xu, Wei; Li, Wenyu; Liu, Ting; Liu, Peng; Zhao, Weili; Zhang, Huilai; Sun, Xiuhua; Yang, Haiyan; Zhang, Xi; Jin, Jie; Jin, Zhengming; Li, Zhiming; Qiu, Lugui; Dong, Mei; Huang, Xiaobing; Luo, Yi; Wang, Xiaodong; Wang, Xin; Wu, Jianqiu; Xu, Jingyan; Yi, Pingyong; Zhou, Jianfeng; He, Hongming; Liu, Lin; Shen, Jianzhen; Tang, Xiaoqiong; Wang, Jinghua; Yang, Jianmin; Zeng, Qingshu; Zhang, Zhihui; Cai, Zhen; Chen, Xiequn; Ding, Kaiyang; Hou, Ming; Huang, Huiqiang; Li, Xiaoling; Liang, Rong; Liu, Qifa; Song, Yuqin; Su, Hang; Gao, Yuhuan; Liu, Lihong; Luo, Jianmin; Su, Liping; Sun, Zimin; Tan, Huo; Wang, Huaqing; Wang, Jingwen; Wang, Shuye; Zhang, Hongyu; Zhang, Xiaohong; Zhou, Daobin; Bai, Ou; Wu, Gang; Zhang, Liling; Zhang, YizhuoJournal of Hematology & Oncology (2017), 10 (), 69/1-69/5CODEN: JHOOAO; ISSN:1756-8722. (BioMed Central Ltd.)The efficacy and safety of chidamide, a new subtype-selective histone deacetylase (HDAC) inhibitor, have been demonstrated in a pivotal phase II clin. trial, and chidamide has been approved by the China Food and Drug Administration (CFDA) as a treatment for relapsed or refractory peripheral T cell lymphoma (PTCL). This study sought to further evaluate the real-world utilization of chidamide in 383 relapsed or refractory PTCL patients from Apr. 2015 to Feb. 2016 in mainland China. For patients receiving chidamide monotherapy (n = 256), the overall response rate (ORR) and disease control rate (DCR) were 39.06 and 64.45%, resp. The ORR and DCR were 51.18 and 74.02%, resp., for patients receiving chidamide combined with chemotherapy (n = 127). For patients receiving chidamide monotherapy and chidamide combined with chemotherapy, the median progression-free survival (PFS) was 129 (95% CI 82 to 194) days for the monotherapy group and 152 (95% CI 93 to 201) days for the combined therapy group (P = 0.3266). Most adverse events (AEs) were of grade 1 to 2. AEs of grade 3 or higher that occurred in ≥5% of patients receiving chidamide monotherapy included thrombocytopenia (10.2%) and neutropenia (6.2%). For patients receiving chidamide combined with chemotherapy, grade 3 to 4 AEs that occurred in ≥5% of patients included thrombocytopenia (18.1%), neutropenia (12.6%), anemia (7.1%), and fatigue (5.5%). This large real-world study demonstrates that chidamide has a favorable efficacy and an acceptable safety profile for refractory and relapsed PTCL patients. Chidamide combined with chemotherapy may be a new treatment choice for refractory and relapsed PTCL patients but requires further investigation.
- 99Lu, X.; Ning, Z.; Li, Z.; Cao, H.; Wang, X. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis. Res. 2016, 5, 185– 191, DOI: 10.5582/irdr.2016.01024[Crossref], [PubMed], [CAS], Google Scholar99https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2svkt1Cnsg%253D%253D&md5=5c1f310ea15bb4a706f54d5fdc55c7d5Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in ChinaLu Xianping; Ning Zhiqiang; Li Zhibin; Cao Haixiang; Wang XinhaoIntractable & rare diseases research (2016), 5 (3), 185-91 ISSN:2186-3644.Peripheral T-cell lymphoma (PTCL) is a set of rare and highly heterogeneous group of mature T- and NK-cell neoplasms associated with poor outcomes and lack of standard and effective therapies. The total number of newly diagnosed cases of PTCL yearly in China is estimated about 50,000. Chidamide (CS055) is a novel and orally active benzamide class of histone deacetylase (HDAC) inhibitor that selectively inhibits activity of HDAC1, 2, 3 and 10, the enzymes that are involved and play an important role in tumor initiation and development in both tumor cells and their surrounding micro-environment. Functioning as a genuine epigenetic modulator, chidamide induces growth arrest and apoptosis in tumor cells and enhances cellular antitumor immunity. Based on the overall results from preclinical and phase I clinical studies, exploratory and pivotal phase II trials of chidamide for relapsed or refractory PTCL were conducted from March 2009 to May 2012, and the results led to CFDA approval of chidamide for the indication in December 2014, being the first approved orphan drug according to the research & development approach of orphan drugs in China, as well as the first orally active drug for PTCL in China and worldwide.
- 100Richards, D. A.; Boehm, K. A.; Waterhouse, D. M.; Wagener, D. J.; Krishnamurthi, S. S.; Rosemurgy, A.; Grove, W.; Macdonald, K.; Gulyas, S.; Clark, M.; Dasse, K. D. Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study. Ann. Oncol. 2006, 17, 1096– 1102, DOI: 10.1093/annonc/mdl081[Crossref], [PubMed], [CAS], Google Scholar100https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD28zotVakug%253D%253D&md5=d1c9da13030a47407ffc93a2fdf8a5fdGemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter studyRichards D A; Boehm K A; Waterhouse D M; Wagener D J; Krishnamurthi S S; Rosemurgy A; Grove W; Macdonald K; Gulyas S; Clark M; Dasse K DAnnals of oncology : official journal of the European Society for Medical Oncology (2006), 17 (7), 1096-102 ISSN:0923-7534.BACKGROUND: CI-994, an oral histone deacetylase inhibitor, has antineoplastic activity and synergism with gemcitabine preclinically. This randomized phase II trial explored whether CI-994 plus gemcitabine improves overall survival, objective response, duration of response, time to treatment failure and change in quality of life (QoL) or pain compared with gemcitabine alone. PATIENTS AND METHODS: A total of 174 patients received CG (CI-994 6 mg/m(2)/day days 1-21 plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 each 28-day cycle) or PG (placebo plus gemcitabine 1000 mg/m(2) days 1, 8 and 15 of each 28-day cycle days 1-21). RESULTS: Median survival was 194 days (CG) versus 214 days (PG) (P = 0.908). The objective response rate with CG was 12% versus 14% with PG when investigator-assessed and 1% versus 6%, respectively, when assessed centrally. Time to treatment failure did not differ between the two arms (P = 0.304). QoL scores at 2 months were worse with CG than with PG. Pain response rates were similar between the two groups. There was an increased incidence of neutropenia and thrombocytopenia with CG. CONCLUSIONS: Adding CI-994 to gemcitabine in advanced pancreatic carcinoma does not improve overall survival, response rate or time to progression; CG produced decreased QoL and increased hematological toxicity and appears inferior to single-agent gemcitabine.
- 101Hauschild, A.; Trefzer, U.; Garbe, C.; Kaehler, K. C.; Ugurel, S.; Kiecker, F.; Eigentler, T.; Krissel, H.; Schott, A.; Schadendorf, D. Multicenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanoma. Melanoma Res. 2008, 18, 274– 278, DOI: 10.1097/CMR.0b013e328307c248[Crossref], [PubMed], [CAS], Google Scholar101https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXosFWnur8%253D&md5=bcbe4c6a1d13dfbc1e93315b703f982fMulticenter phase II trial of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate in pretreated metastatic melanomaHauschild, Axel; Trefzer, Uwe; Garbe, Claus; Kaehler, Katharina C.; Ugurel, Selma; Kiecker, Felix; Eigentler, Thomas; Krissel, Heiko; Schott, Astrid; Schadendorf, DirkMelanoma Research (2008), 18 (4), 274-278CODEN: MREEEH; ISSN:0960-8931. (Lippincott Williams & Wilkins)Systemic treatment of metastatic melanoma is of low efficacy, and new therapeutic strategies are needed. Histone deacetylase inhibitors are supposed to restore the expression of tumor suppressor genes and induce tumor cell differentiation, growth arrest, and apoptosis. This study was aimed to evaluate the efficacy, safety, and pharmacokinetics of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) in patients with pretreated metastatic melanoma. Patients with unresectable AJCC stage IV melanoma refractory to at least one earlier systemic therapy were randomized to receive MS-275 3 mg biweekly (days 1+15, arm A) or 7 mg weekly (days 1+8+15, arm B), in 4-wk cycles. The primary study endpoint was objective tumor response, secondary endpoints were safety and time-to-progression. On the basis of Simon's two-stage design, the study initially allowed an entry of 14 patients per arm; if there was at least one responder, addnl. 33 patients were to be enrolled. Among 28 patients enrolled, no objective response was detected. Four (29%) patients in arm A and three (21%) patients in arm B showed disease stabilizations. Median time-to-progression was comparable in both arms with 55.5 vs. 51.5 days, resp.; median overall survival was 8.84 mo. Toxicity was mild to moderate with nausea (39%) and hypophosphatemia (29%) as the most frequently reported events. No treatment-related serious adverse events occurred. Single-agent treatment with MS-275 was well-tolerated and showed long-term tumor stabilizations, but no objective responses in pretreated metastatic melanoma. Further evaluation of MS-275 in combination schedules is warranted.
- 102Batlevi, C. L.; Kasamon, Y.; Bociek, R. G.; Lee, P.; Gore, L.; Copeland, A.; Sorensen, R.; Ordentlich, P.; Cruickshank, S.; Kunkel, L.; Buglio, D.; Hernandez-Ilizaliturri, F.; Younes, A. ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphoma. Haematologica 2016, 101, 968– 975, DOI: 10.3324/haematol.2016.142406[Crossref], [PubMed], [CAS], Google Scholar102https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhs1aqsrnK&md5=ff56afc5c31a8693aa42eccb400cfef6ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory Hodgkin lymphomaBatlevi, Connie Lee; Kasamon, Yvette; Bociek, R. Gregory; Lee, Peter; Gore, Lia; Copeland, Amanda; Sorensen, Rachel; Ordentlich, Peter; Cruickshank, Scott; Kunkel, Lori; Buglio, Daniela; Hernandez-Ilizaliturri, Francisco; Younes, AnasHaematologica (2016), 101 (8), 968-975CODEN: HAEMAX; ISSN:1592-8721. (Ferrata Storti Foundation)Classical Hodgkin lymphoma treatment is evolving rapidly with high response rates from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response, therefore development of novel therapies is warranted to improve patient outcomes. In this phase II study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat, an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled: 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week); 16 patients on Schedule B (15 mg oral entinostat once weekly in 3 of 4 wk). Patients received a median of 3 prior treatments (range 1-10), with 80% of the patients receiving a prior stem cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention-to-treat anal., the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease beyond 6 mo) was 24%. Seven patients did not complete the first cycle due to progression of disease. Tumor redn. was obsd. in 24 of 38 (58%) evaluable patients. Median progression-free survival and overall survival was 5.5 and 25.1 mo, resp. The most frequent grade 3 or 4 adverse events were thrombocytopenia (63%), anemia (47%), neutropenia (41%), leukopenia (10%), hypokalemia (8%), and hypophosphatemia (6%). Twenty-five (51%) patients required dose redns. or delays. Pericarditis/pericardial effusion occurred in one patient after 12 cycles of therapy. Future studies are warranted to identify predictive biomarkers for treatment response and to develop mechanism-based combination strategies.
- 103Pili, R.; Quinn, D. I.; Hammers, H. J.; Monk, P.; George, S.; Dorff, T. B.; Olencki, T.; Shen, L.; Orillion, A.; Lamonica, D.; Fragomeni, R. S.; Szabo, Z.; Hutson, A.; Groman, A.; Perkins, S. M.; Piekarz, R.; Carducci, M. A. Immunomodulation by entinostat in renal cell carcinoma patients receiving high-dose interleukin 2: A multicenter, single-arm, phase I/II trial (NCI-CTEP#7870). Clin. Cancer Res. 2017, 23, 7199– 7208, DOI: 10.1158/1078-0432.CCR-17-1178[Crossref], [PubMed], [CAS], Google Scholar103https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvFWht7zN&md5=c8e1ddb8639f4b3b57ccc239eafd4b30Immunomodulation by Entinostat in Renal Cell Carcinoma Patients Receiving High-Dose Interleukin 2: A Multicenter, Single-Arm, Phase I/II Trial (NCI-CTEP#7870)Pili, Roberto; Quinn, David I.; Hammers, Hans J.; Monk, Paul; George, Saby; Dorff, Tanya B.; Olencki, Thomas; Shen, Li; Orillion, Ashley; Lamonica, Dominick; Fragomeni, Roberto S.; Szabo, Zsolt; Hutson, Alan; Groman, Adrienne; Perkins, Susan M.; Piekarz, Richard; Carducci, Michael A.Clinical Cancer Research (2017), 23 (23), 7199-7208CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)Purpose: On the basis of preclin. data suggesting that the class I selective HDAC inhibitor entinostat exerts a synergistic antitumor effect in combination with high-dose IL2 in a renal cell carcinoma model by downregulating Foxp3 expression and function of regulatory T cells (Treg), we conducted a phase I/II clin. study with entinostat and high-dose IL2 in patients with metastatic clear cell renal cell carcinoma (ccRCC). Exptl. Design: Clear cell histol., no prior treatments, and being sufficiently fit to receive high-dose IL2 were the main eligibility criteria. The phase I portion consisted of two dose levels of entinostat (3 and 5 mg, orally every 14 days) and a fixed std. dose of IL2 (600,000 U/kg i.v.). Each cycle was 85 days. The primary endpoint was objective response rate and toxicity. Secondary endpoints included progression-free survival and overall survival. Results: Forty-seven patients were enrolled. At a median follow-up of 21.9 mo, the objective response rate was 37% [95% confidence interval (CI), 22%-53%], the median progression-free survival was 13.8 mo (95% CI, 6.0-18.8), and the median overall survival was 65.3 mo (95% CI, 52.6.-65.3). The most common grade 3/4 toxicities were hypophosphatemia (16%), lymphopenia (15%), and hypocalcemia (7%), and all were transient. Decreased Tregs were obsd. following treatment with entinostat, and lower nos. were assocd. with response (P = 0.03). Conclusions: This trial suggests a promising clin. activity for entinostat in combination with high-dose IL2 in ccRCC patients and provides the first example of an epigenetic agent being rationally combined with immunotherapy. Clin Cancer Res; 23(23); 7199-208. ©2017 AACR.
- 104Younes, A.; Oki, Y.; Bociek, R. G.; Kuruvilla, J.; Fanale, M.; Neelapu, S.; Copeland, A.; Buglio, D.; Galal, A.; Besterman, J.; Li, Z.; Drouin, M.; Patterson, T.; Ward, M. R.; Paulus, J. K.; Ji, Y.; Medeiros, L. J.; Martell, R. E. Mocetinostat for relapsed classical Hodgkin’s lymphoma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2011, 12, 1222– 1228, DOI: 10.1016/S1470-2045(11)70265-0[Crossref], [PubMed], [CAS], Google Scholar104https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhsFGjt77O&md5=c6f7748fe47bad8522fb16ef67195231Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trialYounes, Anas; Oki, Yasuhiro; Bociek, R. Gregory; Kuruvilla, John; Fanale, Michelle; Neelapu, Sattva; Copeland, Amanda; Buglio, Daniela; Galal, Ahmed; Besterman, Jeffrey; Li, Zuomei; Drouin, Michel; Patterson, Tracy; Ward, M. Renee; Paulus, Jessica K.; Ji, Yuan; Medeiros, L. Jeffrey; Martell, Robert E.Lancet Oncology (2011), 12 (13), 1222-1228CODEN: LOANBN; ISSN:1470-2045. (Elsevier Ltd.)Summary: Background: The prognosis of patients with relapsed Hodgkin's lymphoma, esp. those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma. Methods: Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per wk, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analyzed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, no. NCT00358982. Findings: 51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose redns. were necessary in the 110 mg cohort, we treated 28 addnl. patients with a dose of 85 mg. On the basis of intent-to-treat anal., the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment. Interpretation: Mocetinostat, 85 mg three times per wk, has promising single-agent clin. activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma. Funding: MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA.
- 105Batlevi, C. L.; Crump, M.; Andreadis, C.; Rizzieri, D.; Assouline, S. E.; Fox, S.; van der Jagt, R. H. C.; Copeland, A.; Potvin, D.; Chao, R.; Younes, A. A phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphoma. Br. J. Haematol. 2017, 178, 434– 441, DOI: 10.1111/bjh.14698[Crossref], [PubMed], [CAS], Google Scholar105https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1SmsLbP&md5=eafed027b27b4e9eb1b2226c8eb88aabA phase 2 study of mocetinostat, a histone deacetylase inhibitor, in relapsed or refractory lymphomaBatlevi, Connie L.; Crump, Michael; Andreadis, Charalambos; Rizzieri, David; Assouline, Sarit E.; Fox, Susan; van der Jagt, Richard H. C.; Copeland, Amanda; Potvin, Diane; Chao, Richard; Younes, AnasBritish Journal of Haematology (2017), 178 (3), 434-441CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Summary: Deregulation of histone deacetylase (HDAC) is important in the pathogenesis of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Mocetinostat, an isotype-selective HDAC inhibitor, induces accumulation of acetylated histones, cell cycle arrest and apoptosis in several cancers. This phase 2 study evaluated mocetinostat in patients with relapsed/refractory (R/R) DLBCL and FL. Seventy-two patients received mocetinostat (starting doses: 70-110 mg TIW, 4-wk cycles). The best overall response rate (95% CI) was 18·9% (7·2, 32·2) for the DLBCL cohort (n = 41), and 11·5% (1·7, 20·7) for the FL cohort (n = 31). Responses were durable (≥90 days in 7 of 10 responses). Overall, 54·1% and 73·1% of patients derived clin. benefit (response or stable disease) from mocetinostat in the DLBCL and FL cohorts, resp. Progression-free survival ranged from 1·8 to 22·8 mo and 11·8 to 26·3 mo in responders with DLBCL and FL, resp. The most frequent treatment-related adverse events were fatigue (75·0%), nausea (69·4%) and diarrhea (61·1%). Although mocetinostat had limited single-agent activity in R/R DLBCL and FL, patients with clin. benefit had long-term disease control. The safety profile was acceptable. This drug class warrants further investigation, including identifying patients more likely to respond to this agent, or in combination with other agents.
- 106Tresckow, B.; Sayehli, C.; Aulitzky, W. E.; Goebeler, M. E.; Schwab, M.; Braz, E.; Krauss, B.; Krauss, R.; Hermann, F.; Bartz, R.; Engert, A. Phase I study of domatinostat (4SC-202), a class I histone deacetylase inhibitor in patients with advanced hematological malignancies. Eur. J. Haematol. 2019, 102, 163– 173, DOI: 10.1111/ejh.13188
- 107Shimony, S.; Horowitz, N.; Ribakovsky, E.; Rozovski, U.; Avigdor, A.; Zloto, K.; Berger, T.; Avivi, I.; Perry, C.; Abadi, U.; Raanani, P.; Gafter-Gvili, A.; Gurion, R. Romidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma: Real-life data from a national multicenter observational study. Hematol. Oncol. 2019, 37, 569– 577, DOI: 10.1002/hon.2691[Crossref], [PubMed], [CAS], Google Scholar107https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXpsFGmtw%253D%253D&md5=fcace7d754fb4c564b95a82b702eae6bRomidepsin treatment for relapsed or refractory peripheral and cutaneous T-cell lymphoma: Real-life data from a national multicenter observational studyShimony, Shai; Horowitz, Netanel; Ribakovsky, Elena; Rozovski, Uri; Avigdor, Abraham; Zloto, Keren; Berger, Tamar; Avivi, Irit; Perry, Chava; Abadi, Uri; Raanani, Pia; Gafter-Gvili, Anat; Gurion, RonitHematological Oncology (2019), 37 (5), 569-577CODEN: HAONDL; ISSN:0278-0232. (Wiley-Blackwell)Currently, there is paucity of real-life data on efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival, event-free survival, overall response rate, complete response and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 mo, EFS was 1.9 mo, ORR rate was 33%, and 12.5% achieved CR. In a univariate anal., predictors for longer EFS include any response to therapy, no. of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate anal. for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematol. Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of pivotal phase II trials. PTCL subtype and the no. of previous lines of therapy have impact on EFS. In addn., patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.
- 108Atadja, P. Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challenges. Cancer Lett. 2009, 280, 233– 241, DOI: 10.1016/j.canlet.2009.02.019[Crossref], [PubMed], [CAS], Google Scholar108https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmsF2jtL4%253D&md5=4c487a2f8dc13f72cecf105d9fae97d9Development of the pan-DAC inhibitor panobinostat (LBH589): Successes and challengesAtadja, PeterCancer Letters (Shannon, Ireland) (2009), 280 (2), 233-241CODEN: CALEDQ; ISSN:0304-3835. (Elsevier Ireland Ltd.)A review. The histone deacetylase (HDAC) inhibitors are emerging as a highly useful class of anticancer agents that inhibit the enzyme HDAC involved in the deacetylation of histone and non-histone cellular proteins. The HDAC inhibitor, panobinostat (LBH589, Novartis Pharmaceuticals), achieves potent inhibition of all HDAC enzymes implicated in cancer and has demonstrated potent anti-tumor activity in preclin. models and promising clin. efficacy in cancer patients. In this review we discuss the successes and challenges surrounding the development of panobinostat, focusing on its proposed mechanism of action, preclin. anti-tumor activity, and early clin. efficacy in hematol. and solid tumors.
- 109Wang, Y.; Stowe, R. L.; Pinello, C. E.; Tian, G.; Madoux, F.; Li, D.; Zhao, L. Y.; Li, J. L.; Wang, Y.; Wang, Y.; Ma, H.; Hodder, P.; Roush, W. R.; Liao, D. Identification of histone deacetylase inhibitors with benzoylhydrazide scaffold that selectively inhibit class I histone deacetylases. Chem. Biol. 2015, 22, 273– 284, DOI: 10.1016/j.chembiol.2014.12.015[Crossref], [PubMed], [CAS], Google Scholar109https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjtlWjsrg%253D&md5=b4e40e24ebe7e1ee7f6f1dacefaa5a39Identification of Histone Deacetylase Inhibitors with Benzoylhydrazide Scaffold that Selectively Inhibit Class I Histone DeacetylasesWang, Yunfei; Stowe, Ryan L.; Pinello, Christie E.; Tian, Guimei; Madoux, Franck; Li, Dawei; Zhao, Lisa Y.; Li, Jian-Liang; Wang, Yuren; Wang, Yuan; Ma, Haiching; Hodder, Peter; Roush, William R.; Liao, DaiqingChemistry & Biology (Oxford, United Kingdom) (2015), 22 (2), 273-284CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Inhibitors of histone deacetylases (HDACi) hold considerable therapeutic promise as clin. anticancer therapies. However, currently known HDACi exhibit limited isoform specificity, off-target activity, and undesirable pharmaceutical properties. Thus, HDACi with new chemotypes are needed to overcome these limitations. Here, we identify a class of HDACi with a previously undescribed benzoylhydrazide scaffold that is selective for the class I HDACs. These compds. are competitive inhibitors with a fast-on/slow-off HDAC-binding mechanism. We show that the lead compd., UF010, inhibits cancer cell proliferation via class I HDAC inhibition. This causes global changes in protein acetylation and gene expression, resulting in activation of tumor suppressor pathways and concurrent inhibition of several oncogenic pathways. The isotype selectivity coupled with interesting biol. activities in suppressing tumor cell proliferation support further preclin. development of the UF010 class of compds. for potential therapeutic applications.
- 110Ho, T. C. S.; Chan, A. H. Y.; Ganesan, A. Thirty years of hdac inhibitors: 2020 insight and hindsight. J. Med. Chem. 2020, 63, 12460– 12484, DOI: 10.1021/acs.jmedchem.0c00830[ACS Full Text], [CAS], Google Scholar110https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtlSisrzP&md5=1deb2ad5787797a9ee98dcf7bdade52cThirty Years of HDAC Inhibitors: 2020 Insight and HindsightHo, Terence C. S.; Chan, Alex H. Y.; Ganesan, A.Journal of Medicinal Chemistry (2020), 63 (21), 12460-12484CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A review. It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clin. development for oncol. as well as other therapeutic indications. This Perspective reviews the biol. and medicinal chem. advances over the past 3 decades with an emphasis on the design of selective inhibitors that discriminate between the 11 human HDAC isoforms.
- 111Mandl-Weber, S.; Meinel, F. G.; Jankowsky, R.; Oduncu, F.; Schmidmaier, R.; Baumann, P. The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cells. Br. J. Haematol. 2010, 149, 518– 528, DOI: 10.1111/j.1365-2141.2010.08124.x[Crossref], [PubMed], [CAS], Google Scholar111https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXns1eqt70%253D&md5=16b57835f5e5d19d8cd587b299820d98The novel inhibitor of histone deacetylase resminostat (RAS2410) inhibits proliferation and induces apoptosis in multiple myeloma (MM) cellsMandl-Weber, Sonja; Meinel, Felix G.; Jankowsky, Ruediger; Oduncu, Fuat; Schmidmaier, Ralf; Baumann, PhilippBritish Journal of Haematology (2010), 149 (4), 518-528CODEN: BJHEAL; ISSN:0007-1048. (Wiley-Blackwell)Inhibition of histone deacetylase (HDAC) is a promising mechanism for novel, anti-myeloma agents. We investigated the effects of the novel HDAC inhibitor resminostat on multiple myeloma (MM) cells in vitro. Resminostat is a potent inhibitor of HDACs 1, 3 and 6 [50% inhibitory concn. (IC50) = 43-72 nmol/l] representing HDAC classes I and II and induces hyperacetylation of histone H4 in MM cells. Low micromolar concns. of resminostat abrogated cell growth and strongly induced apoptosis (IC50 = 2·5-3 μmol/l in 3 out of 4 MM cell lines) in MM cell lines as well as primary MM cells. At 1 μmol/l, resminostat inhibited proliferation and induced G0/G1 cell cycle arrest in 3 out of 4 MM cell lines accompanied with decreased levels of cyclin D1, cdc25a, Cdk4 and pRb as well as upregulation of p21. Resminostat decreased phosphorylation of 4E-BP1 and p70S6k indicating an interference with Akt pathway signalling. Treatment with resminostat resulted in increased protein levels of Bim and Bax and decreased levels of Bcl-xL. Caspases 3, 8 and 9 were activated by resminostat. Furthermore, synergistic effects were obsd. for combinations of resminostat with melphalan and the proteasome inhibitors bortezomib and S-2209. In conclusion, we have identified potent anti-myeloma activity for this novel HDAC inhibitor.
- 112Novotny-Diermayr, V.; Sangthongpitag, K.; Hu, C. Y.; Wu, X.; Sausgruber, N.; Yeo, P.; Greicius, G.; Pettersson, S.; Liang, A. L.; Loh, Y. K.; Bonday, Z.; Goh, K. C.; Hentze, H.; Hart, S.; Wang, H.; Ethirajulu, K.; Wood, J. M. SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer. Mol. Cancer Ther. 2010, 9, 642– 652, DOI: 10.1158/1535-7163.MCT-09-0689[Crossref], [PubMed], [CAS], Google Scholar112https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXivFens7Y%253D&md5=ffe0b917c40862c4ca0b414c8ef4c493SB939, a Novel Potent and Orally Active Histone Deacetylase Inhibitor with High Tumor Exposure and Efficacy in Mouse Models of Colorectal CancerNovotny-Diermayr, Veronica; Sangthongpitag, Kanda; Hu, Chang Yong; Wu, Xiaofeng; Sausgruber, Nina; Yeo, Pauline; Greicius, Gediminas; Pettersson, Sven; Liang, Ai Leng; Loh, Yung Kiang; Bonday, Zahid; Goh, Kee Chuan; Hentze, Hannes; Hart, Stefan; Wang, Haishan; Ethirajulu, Kantharaj; Wood, Jeanette MarjorieMolecular Cancer Therapeutics (2010), 9 (3), 642-652CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Although clin. responses in liq. tumors and certain lymphomas have been reported, the clin. efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concns. of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochem., pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% vs. 48% for SAHA (both at max. tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APCmin mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clin. data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacol. advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients. Mol Cancer Ther; 9(3); 642-52.
- 113Cai, X.; Zhai, H. X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai, C. J.; Bao, R.; Qian, C. Discovery of 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer. J. Med. Chem. 2010, 53, 2000– 2009, DOI: 10.1021/jm901453q[ACS Full Text], [CAS], Google Scholar113https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhslSgsb0%253D&md5=d4dc339f2fd750d52e511abf3dbf18bdDiscovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of CancerCai, Xiong; Zhai, Hai-Xiao; Wang, Jing; Forrester, Jeffrey; Qu, Hui; Yin, Ling; Lai, Cheng-Jung; Bao, Rudi; Qian, ChanggengJournal of Medicinal Chemistry (2010), 53 (5), 2000-2009CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compds. with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clin. development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, resp. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compd. that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
- 114Ning, Z. Q.; Li, Z. B.; Newman, M. J.; Shan, S.; Wang, X. H.; Pan, D. S.; Zhang, J.; Dong, M.; Du, X.; Lu, X. P. Chidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicity. Cancer Chemother. Pharmacol. 2012, 69, 901– 909, DOI: 10.1007/s00280-011-1766-x[Crossref], [PubMed], [CAS], Google Scholar114https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XkvVCrsr4%253D&md5=a0055f5a84ad0a9d8d1bd907339cab0fChidamide (CS055/HBI-8000): a new histone deacetylase inhibitor of the benzamide class with antitumor activity and the ability to enhance immune cell-mediated tumor cell cytotoxicityNing, Zhi-Qiang; Li, Zhi-Bin; Newman, Michael J.; Shan, Song; Wang, Xin-Hao; Pan, De-Si; Zhang, Jin; Dong, Mei; Du, Xin; Lu, Xian-PingCancer Chemotherapy and Pharmacology (2012), 69 (4), 901-909CODEN: CCPHDZ; ISSN:0344-5704. (Springer)Purpose. Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor of the benzamide class currently under clin. development in cancer indications. This study reports the in vitro and in vivo antitumor characteristics of the compd. Methods. Selectivity and potency of chidamide in inhibition of HDAC isotypes were analyzed by using a panel of human recombinant HDAC proteins. Tumor cell lines either in culture or inoculated in nude mice were used for the evaluation of the compd.'s antitumor activity. To investigate the immune cell-mediated antitumor effect, isolated peripheral blood mononuclear cells from healthy donors were treated with chidamide, and cytotoxicity and expression of relevant surface proteins were analyzed. Microarray gene expression studies were performed on peripheral white blood cells from two T-cell lymphoma patients treated with chidamide. Results. Chidamide was found to be a low nanomolar inhibitor of HDAC1, 2, 3, and 10, the HDAC isotypes well documented to be assocd. with the malignant phenotype. Significant and broad spectrum in vitro and in vivo antitumor activity, including a wide therapeutic index, was obsd. Chidamide was also shown to enhance the cytotoxic effect of human peripheral mononuclear cells ex vivo on K562 target cells, accompanied by the upregulation of proteins involved in NK cell functions. Furthermore, the expression of a no. of genes involved in immune cell-mediated antitumor activity was obsd. to be upregulated in peripheral white blood cells from two T-cell lymphoma patients who responded to chidamide administration. Conclusions. The results presented in this study provide evidence that chidamide has potential applicability for the treatment of a variety of tumor types, either as a single agent or in combination therapies.
- 115Fournel, M.; Bonfils, C.; Hou, Y.; Yan, P. T.; Trachy-Bourget, M. C.; Kalita, A.; Liu, J.; Lu, A. H.; Zhou, N. Z.; Robert, M. F.; Gillespie, J.; Wang, J. J.; Ste-Croix, H.; Rahil, J.; Lefebvre, S.; Moradei, O.; Delorme, D.; Macleod, A. R.; Besterman, J. M.; Li, Z. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 2008, 7, 759– 768, DOI: 10.1158/1535-7163.MCT-07-2026[Crossref], [PubMed], [CAS], Google Scholar115https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXks1Gms70%253D&md5=48604f141d969585efaa71c4005496cfMGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivoFournel, Marielle; Bonfils, Claire; Hou, Yu; Yan, Pu Theresa; Trachy-Bourget, Marie-Claude; Kalita, Ann; Liu, Jianhong; Lu, Ai-Hua; Zhou, Nancy Z.; Robert, Marie-France; Gillespie, Jeffrey; Wang, James J.; Ste-Croix, Helene; Rahil, Jubrail; Lefebvre, Sylvain; Moradei, Oscar; Delorme, Daniel; MacLeod, A. Robert; Besterman, Jeffrey M.; Li, ZuomeiMolecular Cancer Therapeutics (2008), 7 (4), 759-768CODEN: MCTOCF; ISSN:1535-7163. (American Association for Cancer Research)Nonselective inhibitors of human histone deacetylases (HDAC) are known to have antitumor activity in mice in vivo, and several of them are under clin. investigation. The first of these, Vorinostat (SAHA), has been approved for treatment of cutaneous T-cell lymphoma. Questions remain concerning which HDAC isotype(s) are the best to target for anticancer activity and whether increased efficacy and safety will result with an isotype-selective HDAC inhibitor. We have developed an isotype-selective HDAC inhibitor, MGCD0103, which potently targets human HDAC1 but also has inhibitory activity against HDAC2, HDAC3, and HDAC11 in vitro. In intact cells, MGCD0103 inhibited only a fraction of the total HDAC activity and showed long-lasting inhibitory activity even upon drug removal. MGCD0103 induced hyperacetylation of histones, selectively induced apoptosis, and caused cell cycle blockade in various human cancer cell lines in a dose-dependent manner. MGCD0103 exhibited potent and selective antiproliferative activities against a broad spectrum of human cancer cell lines in vitro, and HDAC inhibitory activity was required for these effects. In vivo, MGCD0103 significantly inhibited growth of human tumor xenografts in nude mice in a dose-dependent manner and the antitumor activity correlated with induction of histone acetylation in tumors. Our findings suggest that the isotype-selective HDAC inhibition by MGCD0103 is sufficient for antitumor activity in vivo and that further clin. investigation is warranted. [Mol Cancer Ther 2008;7(4):759-68].
- 116Pinkerneil, M.; Hoffmann, M. J.; Kohlhof, H.; Schulz, W. A.; Niegisch, G. Evaluation of the therapeutic potential of the novel isotype specific HDAC inhibitor 4SC-202 in urothelial carcinoma cell lines. Target Oncol. 2016, 11, 783– 798, DOI: 10.1007/s11523-016-0444-7[Crossref], [PubMed], [CAS], Google Scholar116https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2s%252FlslWjsQ%253D%253D&md5=8decc6b1e3ff3d96fc12e0661246fe7cEvaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell LinesPinkerneil Maria; Hoffmann Michele J; Schulz Wolfgang A; Niegisch Gunter; Kohlhof HellaTargeted oncology (2016), 11 (6), 783-798 ISSN:.BACKGROUND: Targeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models. AIM: The aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines. METHODS: We determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control. RESULTS: 4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15-0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment. CONCLUSION: Specific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC.
- 117Subramanian, S.; Bates, S. E.; Wright, J. J.; Espinoza-Delgado, I.; Piekarz, R. L. Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals 2010, 3, 2751– 2767, DOI: 10.3390/ph3092751[Crossref], [PubMed], [CAS], Google Scholar117https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFSmtrvK&md5=d0937756ff0e5582c1e33901c913ff97Clinical toxicities of histone deacetylase inhibitorsSubramanian, Srividya; Bates, Susan E.; Wright, John J.; Espinoza-Delgado, Igor; Piekarz, Richard L.Pharmaceuticals (2010), 3 (), 2751-2767CODEN: PHARH2; ISSN:1424-8247. (Molecular Diversity Preservation International)A review. The HDAC inhibitors are a new family of antineoplastic agents. Since the entry of these agents into our therapeutic armamentarium, there has been increasing interest in their use. Although this family comprises chem. compds. from unrelated chem. classes that have different HDAC isoform specificities, they surprisingly have very similar toxicity profiles. In contrast, the obsd. toxicity profile is somewhat different from that of traditional cytotoxic chemotherapeutic agents and from other epigenetic agents. While some of the side effects may be familiar to the oncologist, others are less commonly seen. As some patients remain on therapy for a prolonged period of time, the long-term sequelae need to be characterized. In addn., since preclin. models suggest promising activity when used in combination with other antineoplastic agents, combination trials are being pursued. It will thus be important to distinguish the relative toxicity attributed to these agents and be alert to the exacerbation of toxicities obsd. in single agent studies. Notably, few of the agents in this class have completed phase 2 testing. Consequently, more clin. experience is needed to det. the relative frequency of the obsd. side effects, and to identify and develop approaches to mitigate potential clin. sequelae.
- 118Tan, J.; Cang, S.; Ma, Y.; Petrillo, R. L.; Liu, D. Novel histone deacetylase inhibitors inclinical trials as anti-cancer agents. J. Hematol. Oncol. 2010, 3, 5, DOI: 10.1186/1756-8722-3-5[Crossref], [PubMed], [CAS], Google Scholar118https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC3c7jtFejtg%253D%253D&md5=399a6c058fd597450221aff2648d8c0fNovel histone deacetylase inhibitors in clinical trials as anti-cancer agentsTan Jiahuai; Cang Shundong; Ma Yuehua; Petrillo Richard L; Liu DelongJournal of hematology & oncology (2010), 3 (), 5 ISSN:.Histone deacetylases (HDACs) can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of HDACs. One of the HDAC inhibitors, vorinostat, has been approved by FDA for treating cutaneous T-cell lymphoma (CTCL) for patients with progressive, persistent, or recurrent disease on or following two systemic therapies. Other inhibitors, for example, FK228, PXD101, PCI-24781, ITF2357, MGCD0103, MS-275, valproic acid and LBH589 have also demonstrated therapeutic potential as monotherapy or combination with other anti-tumor drugs in CTCL and other malignancies. At least 80 clinical trials are underway, testing more than eleven different HDAC inhibitory agents including both hematological and solid malignancies. This review focuses on recent development in clinical trials testing HDAC inhibitors as anti-tumor agents.
- 119Taunton, J.; Hassig, C. A.; Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 1996, 272, 408– 411, DOI: 10.1126/science.272.5260.408[Crossref], [PubMed], [CAS], Google Scholar119https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XisVegsr8%253D&md5=fda244b40a10d5bc75f94fcc6fae189fA mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3pTaunton, Jack; Hassig, Christian A.; Schreiber, Stuart L.Science (Washington, D. C.) (1996), 272 (5260), 408-11CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)Trapoxin is a microbially derived cyclotetrapeptide that inhibits histone deacetylation in vivo and causes mammalian cells to arrest in the cell cycle. A trapoxin affinity matrix was used to isolate two nuclear proteins that copurified with histone deacetylase activity. Both proteins were identified by peptide microsequencing, and a complementary DNA encoding the histone deacetylase catalytic subunit (HD1) was cloned from a human Jurkat T cell library. As the predicted protein is very similar to the yeast transcriptional regulator Rpd3p, these results support a role for histone deacetylase as a key regulator of eukaryotic transcription.
- 120Yang, W. M.; Inouye, C.; Zeng, Y.; Bearss, D.; Seto, E. Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3. Proc. Natl. Acad. Sci. U. S. A. 1996, 93, 12845– 12850, DOI: 10.1073/pnas.93.23.12845[Crossref], [PubMed], [CAS], Google Scholar120https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK28XmvV2lsLg%253D&md5=764b34dc10cc26e04cd7460b6149ebc3Transcriptional repression by YY1 is mediated by interaction with a mammalian homolog of the yeast global regulator RPD3Yang, Wen-Ming; Inouye, Carla; Zeng, Yingying; Bearss, David; Seto, EdwardProceedings of the National Academy of Sciences of the United States of America (1996), 93 (23), 12845-12850CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)YY1 is a mammalian zinc-finger transcription factor with unusual structural and functional features. It has been implicated as a pos. and a neg. regulatory factor that binds to the CCATNTT consensus DNA element located in promoters of many cellular and viral genes. A mammalian cDNA that encodes a YY1-binding protein and possesses sequence homol. with the yeast transcriptional factor RPD3 was identified. A Gal4 DNA binding domain-mammalian RPD3 fusion protein strongly represses transcriptional from a promoter contg. Gal4 binding sites. Assocn. between YY1 and mammalian RPD3 requires a glycine-rich region on YY1. Mutations in this region abolish the interaction with mammalian RPD3 and eliminate transcriptional repression by YY1. These data suggest that YY1 neg. regulates transcription by tethering RPD3 to DNA as a cofactor and that this transcriptional mechanism is highly conserved from yeast to human.
- 121Yang, W. M.; Yao, Y. L.; Sun, J. M.; Davie, J. R.; Seto, E. Isolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene family. J. Biol. Chem. 1997, 272, 28001– 28007, DOI: 10.1074/jbc.272.44.28001[Crossref], [PubMed], [CAS], Google Scholar121https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK2sXnt12lt7s%253D&md5=cf9e3e377ef706b4a49043d54c1ef11aIsolation and characterization of cDNAs corresponding to an additional member of the human histone deacetylase gene familyYang, Wen-Ming; Yao, Ya-Li; Sun, Jian-Min; Davie, James R.; Seto, EdwardJournal of Biological Chemistry (1997), 272 (44), 28001-28007CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Several human cDNAs encoding a histone deacetylase protein, HDAC3, have been isolated. Anal. of the predicted amino acid sequence of HDAC3 revealed an open reading frame of 428 amino acids with a predicted mol. mass of 49 kDa. The HDAC3 protein is 50% identical in DNA sequence and 53% identical in protein sequence compared with the previously cloned human HDAC1. Comparison of the HDAC3 sequence with human HDAC2 also yielded similar results, with 51% identity in DNA sequence and 52% identity in protein sequence. The expressed HDAC3 protein is functionally active because it possesses histone deacetylase activity, represses transcription when tethered to a promoter, and binds transcription factor YY1. Similar to HDAC1 and HDAC2, HDAC3 is ubiquitously expressed in many different cell types.
- 122Thomas, E. A. Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders; Therapeutic implications for selective HDAC1/HDAC3 inhibitors. Pharmaceuticals 2014, 7, 634– 661, DOI: 10.3390/ph7060634[Crossref], [PubMed], [CAS], Google Scholar122https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1CqtrbI&md5=44797d30e06e109682073a9ec7008c50Involvement of HDAC1 and HDAC3 in the pathology of polyglutamine disorders: therapeutic implications for selective HDAC1/HDAC3 inhibitorsThomas, Elizabeth A.Pharmaceuticals (2014), 7 (6), 634-661, 28CODEN: PHARH2; ISSN:1424-8247. (MDPI AG)A review. Histone deacetylases (HDACs) enzymes, which affect the acetylation status of histones and other important cellular proteins, have been recognized as potentially useful therapeutic targets for a broad range of human disorders. Emerging studies have demonstrated that different types of HDAC inhibitors show beneficial effects in various exptl. models of neurol. disorders. HDAC enzymes comprise a large family of proteins, with18 HDAC enzymes currently identified in humans. Hence, an important question for HDAC inhibitor therapeutics is which HDAC enzyme(s) is/are important for the amelioration of disease phenotypes, as it has become clear that individual HDAC enzymes play different biol. roles in the brain. This review will discuss evidence supporting the involvement of HDAC1 and HDAC3 in polyglutamine disorders, including Huntington's disease, and the use of HDAC1- and HDAC3-selective HDAC inhibitors as therapeutic intervention for these disorders. Further, while HDAC inhibitors are known alter chromatin structure resulting in changes in gene transcription, understanding the exact mechanisms responsible for the preclin. efficacy of these compds. remains a challenge. The potential chromatin-related and non-chromatin-related mechanisms of action of selective HDAC inhibitors will also be discussed.
- 123Broide, R. S.; Redwine, J. M.; Aftahi, N.; Young, W.; Bloom, F. E.; Winrow, C. J. Distribution of histone deacetylases 1–11 in the rat brain. J. Mol. Neurosci. 2007, 31, 47– 58, DOI: 10.1007/BF02686117[Crossref], [PubMed], [CAS], Google Scholar123https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXls1GqtL8%253D&md5=8b0ef986705015f17dee856b602a99eaDistribution of histone deacetylases 1-11 in the rat brainBroide, Ron S.; Redwine, Jeff M.; Aftahi, Najla; Young, Warren; Bloom, Floyd E.; Winrow, Christopher J.Journal of Molecular Neuroscience (2007), 31 (1), 47-58CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling mols. is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyltransferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurodegeneration. The authors initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resoln. in situ hybridization (ISH) and imaging technol. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addn., immunohistochem. was performed on these samples to sep. examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled stds. and thereby enabled semiquant. anal. of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examg. the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
- 124Karagianni, P.; Wong, J. HDAC3: taking the SMRT-N-CoRrect road to repression. Oncogene 2007, 26, 5439– 5449, DOI: 10.1038/sj.onc.1210612[Crossref], [PubMed], [CAS], Google Scholar124https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXovFersr4%253D&md5=9632389f7a794442f529b1f71fad8053HDAC3: taking the SMRT-N-CoRrect road to repressionKaragianni, P.; Wong, J.Oncogene (2007), 26 (37), 5439-5449CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the compn., regulation and mechanism of action of the SMRT/N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiol. processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation.
- 125Guenther, M. G.; Barak, O.; Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 2001, 21, 6091– 6101, DOI: 10.1128/MCB.21.18.6091-6101.2001[Crossref], [PubMed], [CAS], Google Scholar125https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXmsFKmtr0%253D&md5=08a7ef9200c66413a373923873b3442cThe SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3Guenther, Matthew G.; Barak, Orr; Lazar, Mitchell A.Molecular and Cellular Biology (2001), 21 (18), 6091-6101CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Repression of gene transcription is linked to regulation of chromatin structure through deacetylation of core histone amino-terminal tails. This action is mediated by histone deacetylases (HDACs) that function within active multiprotein complexes directed to the promoters of repressed genes. In vivo, HDAC3 forms a stable complex with the SMRT corepressor. The SMRT-HDAC3 complex exhibits histone deacetylase activity, whereas recombinant HDAC3 is an inactive enzyme. Here we report that SMRT functions as an activating cofactor of HDAC3. In contrast, SMRT does not activate the class II HDAC4, with which it also interacts. Activation of HDAC3 is mediated by a deacetylase activating domain (DAD) that includes one of two SANT motifs present in SMRT. A cognate DAD is present in the related corepressor N-CoR, which can also activate HDAC3. Mutations in the DAD that abolish HDAC3 interaction also eliminate reconstitution of HDAC activity. Using purified components, the SMRT DAD is shown to be necessary and sufficient for activation of HDAC3. Moreover, the DAD is required both for HDAC3 to function enzymically and for the major repression function of SMRT. Thus, SMRT and N-CoR do not serve merely as platforms for HDAC recruitment but function as an integral component of an active cellular HDAC3 enzyme.
- 126Ishizuka, T.; Lazar, M. A. The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptor. Mol. Cell. Biol. 2003, 23, 5122– 5131, DOI: 10.1128/MCB.23.15.5122-5131.2003[Crossref], [PubMed], [CAS], Google Scholar126https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXlslGnurk%253D&md5=e6374d9cad91e51082a596ab7afe69d9The N-CoR/histone deacetylase 3 complex is required for repression by thyroid hormone receptorIshizuka, Takahiro; Lazar, Mitchell A.Molecular and Cellular Biology (2003), 23 (15), 5122-5131CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)Nuclear receptor corepressors (N-CoR) and silencing mediator for retinoid and thyroid receptors (SMRT) have both been implicated in thyroid hormone receptor (TR)-mediated repression. Here we show that endogenous N-CoR, TBL1, and histone deacetylase 3 (HDAC3), but not HDAC1, -2, or -4, are recruited to a stably integrated reporter gene repressed by unliganded TR as well as the orphan receptor RevErb. Unliganded TR also recruits this complex to a transiently transfected reporter, and transcriptional repression is assocd. with local histone deacetylation that is reversed by the presence of thyroid hormone. Knockdown of N-CoR using small interfering RNAs markedly reduces repression by the TR ligand binding domain in human 293T cells, whereas knockdown of SMRT has little effect. RevErb repression appears to involve both corepressors in this system. Knockdown of HDAC3 markedly reduces repression by both TR and RevErb, while knockdown of HDAC1 or 2 has more modest, partly nonspecific effects. Thus, HDAC3 is crit. for repression by multiple nuclear receptors and the N-CoR HDAC3 complex plays a unique and necessary role in TR-mediated gene repression in human 293T cells.
- 127Yu, J.; Li, Y.; Ishizuka, T.; Guenther, M. G.; Lazar, M. A. A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylation. EMBO J. 2003, 22, 3403– 3410, DOI: 10.1093/emboj/cdg326[Crossref], [PubMed], [CAS], Google Scholar127https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3sXltFyhtLc%253D&md5=92b529e9ba046eabbd075830e394b1d9A SANT motif in the SMRT corepressor interprets the histone code and promotes histone deacetylationYu, Jiujiu; Li, Yun; Ishizuka, Takahiro; Guenther, Matthew G.; Lazar, Mitchell A.EMBO Journal (2003), 22 (13), 3403-3410CODEN: EMJODG; ISSN:0261-4189. (Oxford University Press)Nuclear receptor corepressors SMRT (silencing mediator of retinoid and thyroid receptors) and N-CoR (nuclear receptor corepressor) recruit histone deacetylase (HDAC) activity to targeted regions of chromatin. These corepressors contain a closely spaced pair of SANT motifs whose sequence and organization is highly conserved. The N-terminal SANT is a crit. component of a deacetylase activation domain (DAD) that binds and activates HDAC3. Here, we show that the second SANT motif functions as part of a histone interaction domain (HID). The HID enhances repression by increasing the affinity of the DAD-HDAC3 enzyme for histone substrate. The two SANT motifs synergistically promote histone deacetylation and repression through unique functions. The HID contribution to repression is magnified by its ability to inhibit histone acetyltransferase enzyme activity. Remarkably, the SANT-contg. HID preferentially binds to unacetylated histone tails. This implies that the SMRT HID participates in interpreting the histone code in a feed-forward mechanism that promotes and maintains histone deacetylation at genomic sites of SMRT recruitment.
- 128Hartman, H. B.; Yu, J.; Alenghat, T.; Ishizuka, T.; Lazar, M. A. The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3. EMBO Rep. 2005, 6, 445– 451, DOI: 10.1038/sj.embor.7400391[Crossref], [PubMed], [CAS], Google Scholar128https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjsleru7o%253D&md5=ed0ba38c3767193d2941da0554323805The histone-binding code of nuclear receptor co-repressors matches the substrate specificity of histone deacetylase 3Hartman, Helen B.; Yu, Jiujiu; Alenghat, Theresa; Ishizuka, Takahiro; Lazar, Mitchell A.EMBO Reports (2005), 6 (5), 445-451CODEN: ERMEAX; ISSN:1469-221X. (Nature Publishing Group)Ligands for nuclear receptors facilitate the exchange of co-repressors for coactivators, leading to chromatin modifications that favor the activation of gene transcription. Here, we show that the repressed state of an endogenous retinoic acid-regulated gene is quickly re-established after ligand removal. As expected, repression is characterized by recruitment of N-CoR/SMRT-HDAC3 (histone deacetylase 3) co-repressor complexes, leading to local histone hypoacetylation. The achievement of the repressed state involves the ordered deacetylation of lysines in H4 tails. This order is detd. by the inherent substrate specificity of HDAC3, and unexpectedly predicts the binding preference of N-CoR/SMRT for submaximally acetylated H4 tails. The match between the specificity of acetyl-histone deacetylation by HDAC3 and the histone-binding preference of N-CoR/SMRT allows the co-repressor complex to stabilize and propagate repression of nuclear hormone receptor gene targets.
- 129Bhaskara, S.; Knutson, S. K.; Jiang, G.; Chandrasekharan, M. B.; Wilson, A. J.; Zheng, S.; Yenamandra, A.; Locke, K.; Yuan, J. L.; Bonine-Summers, A. R.; Wells, C. E.; Kaiser, J. F.; Washington, M. K.; Zhao, Z.; Wagner, F. F.; Sun, Z. W.; Xia, F.; Holson, E. B.; Khabele, D.; Hiebert, S. W. HDAC3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 2010, 18, 436– 447, DOI: 10.1016/j.ccr.2010.10.022[Crossref], [PubMed], [CAS], Google Scholar129https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsValtLrM&md5=eecd358b969a1bf6f4c55824c62d2d0fHdac3 Is Essential for the Maintenance of Chromatin Structure and Genome StabilityBhaskara, Srividya; Knutson, Sarah K.; Jiang, Guochun; Chandrasekharan, Mahesh B.; Wilson, Andrew J.; Zheng, Siyuan; Yenamandra, Ashwini; Locke, Kimberly; Yuan, Jia-ling; Bonine-Summers, Alyssa R.; Wells, Christina E.; Kaiser, Jonathan F.; Washington, M. Kay; Zhao, Zhongming; Wagner, Florence F.; Sun, Zu-Wen; Xia, Fen; Holson, Edward B.; Khabele, Dineo; Hiebert, Scott W.Cancer Cell (2010), 18 (5), 436-447CODEN: CCAECI; ISSN:1535-6108. (Cell Press)Summary: Hdac3 is essential for efficient DNA replication and DNA damage control. Deletion of Hdac3 impaired DNA repair and greatly reduced chromatin compaction and heterochromatin content. These defects corresponded to increases in histone H3K9,K14ac; H4K5ac; and H4K12ac in late S phase of the cell cycle, and histone deposition marks were retained in quiescent Hdac3-null cells. Liver-specific deletion of Hdac3 culminated in hepatocellular carcinoma. Whereas HDAC3 expression was downregulated in only a small no. of human liver cancers, the mRNA levels of the HDAC3 cofactor NCOR1 were reduced in 1-third of these cases. SiRNA targeting of NCOR1 and SMRT (NCOR2) increased H4K5ac and caused DNA damage, indicating that the HDAC3/NCOR1/SMRT axis is crit. for maintaining chromatin structure and genomic stability.
- 130Yang, W. M.; Tsai, S. C.; Wen, Y. D.; Fejer, G.; Seto, E. Functional domains of histone deacetylase-3. J. Biol. Chem. 2002, 277, 9447– 9454, DOI: 10.1074/jbc.M105993200[Crossref], [PubMed], [CAS], Google Scholar130https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38Xitl2kt78%253D&md5=2f4ac16a64de4fcad367111a4bd9eeefFunctional domains of histone deacetylase-3Yang, Wen-Ming; Tsai, Shih-Chang; Wen, Yu-Der; Fejer, Gyorgy; Seto, EdwardJournal of Biological Chemistry (2002), 277 (11), 9447-9454CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Post-translational modifications of histones, in general, and acetylation/deacetylation, in particular, can dramatically alter gene expression in eukaryotic cells. In humans, four highly homologous class I HDAC enzymes (HDAC1, HDAC2, HDAC3, and HDAC8) have been identified to date. Although HDAC3 shares some structural and functional similarities with other class I HDACs, it exists in multisubunit complexes sep. and different from other known HDAC complexes, implying that individual HDACs might function in a distinct manner. In this current study, to understand further the cellular function of HDAC3 and to uncover possible unique roles this protein may have in gene regulation, we performed a detailed anal. of HDAC3 using deletion mutations. Surprisingly, we found that the non-conserved C-terminal region of HDAC3 is required for both deacetylase and transcriptional repression activity. In addn., we discovered that the central portion of the HDAC3 protein possesses a nuclear export signal, whereas the C-terminal part of HDAC3 contributes to the protein's localization in the nucleus. Finally, we found that HDAC3 forms oligomers in vitro and in vivo and that the N-terminal portion of HDAC3 is necessary for this property. These data indicate that HDAC3 comprises sep., non-overlapping domains that contribute to the unique properties and function of this protein.
- 131Watson, P. J.; Fairall, L.; Santos, G. M.; Schwabe, J. W. Structure of HDAC3 bound to corepressor and inositol tetraphosphate. Nature 2012, 481, 335– 340, DOI: 10.1038/nature10728[Crossref], [PubMed], [CAS], Google Scholar131https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XlsF2rtg%253D%253D&md5=cac4b2efef5360a2a174e31cfb8a241dStructure of HDAC3 bound to co-repressor and inositol tetraphosphateWatson, Peter J.; Fairall, Louise; Santos, Guilherme M.; Schwabe, John W. R.Nature (London, United Kingdom) (2012), 481 (7381), 335-340CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)Histone deacetylase enzymes (HDACs) are emerging cancer drug targets. They regulate gene expression by removing acetyl groups from lysine residues in histone tails, resulting in chromatin condensation. The enzymic activity of most class I HDACs requires recruitment into multi-subunit co-repressor complexes, which are in turn recruited to chromatin by repressive transcription factors. Here we report the structure of a complex between an HDAC and a co-repressor, namely, human HDAC3 with the deacetylase activation domain (DAD) from the human SMRT co-repressor (also known as NCOR2). The structure reveals two remarkable features. First, the SMRT-DAD undergoes a large structural rearrangement on forming the complex. Second, there is an essential inositol tetraphosphate mol. - D-myo-inositol-(1,4,5,6)-tetrakisphosphate (Ins(1,4,5,6)P4) - acting as an 'intermol. glue' between the two proteins. Assembly of the complex is clearly dependent on the Ins(1,4,5,6)P4, which may act as a regulator - potentially explaining why inositol phosphates and their kinases have been found to act as transcriptional regulators. This mechanism for the activation of HDAC3 appears to be conserved in class I HDACs from yeast to humans, and opens the way to novel therapeutic opportunities.
- 132Wang, D. F.; Helquist, P.; Wiech, N. L.; Wiest, O. Toward selective histone deacetylase inhibitor design: homology modeling, docking studies, and molecular dynamics simulations of human class I histone deacetylases. J. Med. Chem. 2005, 48, 6936– 6947, DOI: 10.1021/jm0505011[ACS Full Text], [CAS], Google Scholar132https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtV2jsLnL&md5=0b59815173df7f16feb9ba66c8b4da83Toward Selective Histone Deacetylase Inhibitor Design: Homology Modeling, Docking Studies, and Molecular Dynamics Simulations of Human Class I Histone DeacetylasesWang, Di-Fei; Helquist, Paul; Wiech, Norbert L.; Wiest, OlafJournal of Medicinal Chemistry (2005), 48 (22), 6936-6947CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Histone deacetylases (HDACs) play an important role in gene transcription. Inhibitors of HDACs induce cell differentiation and suppress cell proliferation in tumor cells. Although many HDAC inhibitors have been designed and synthesized, selective inhibition for class I HDAC isoforms is a goal that has yet to be achieved. To understand the difference between class I HDAC isoforms that could be exploited for the design of isoform-specific HDAC inhibitors, the authors have built three-dimensional models of four class I histone deacetylases, HDAC1, HDAC2, HDAC3, and HDAC8. Comparison of the homol. model of HDAC8 with the recently published x-ray structure shows excellent agreement and validates the approach. A series of HDAC inhibitors were docked to the homol. models to understand the similarities and differences between the binding modes. Mol. dynamic simulations of these HDAC-inhibitor complexes indicate that the interaction between the protein surface and inhibitor is playing an important role; also some active site residues show some flexibility, which is usually not included in routine docking protocols. The implications of these results for the design of isoform-selective HDAC inhibitors are discussed.
- 133Zhang, X.; Zhao, X.; Fiskus, W.; Lin, J.; Lwin, T.; Rao, R.; Zhang, Y.; Chan, J. C.; Fu, K.; Marquez, V. E.; Chen-Kiang, S.; Moscinski, L. C.; Seto, E.; Dalton, W. S.; Wright, K. L.; Sotomayor, E.; Bhalla, K.; Tao, J. Coordinated silencing of Myc-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-Cell lymphomas. Cancer Cell 2012, 22, 506– 523, DOI: 10.1016/j.ccr.2012.09.003[Crossref], [PubMed], [CAS], Google Scholar133https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhsFWitLnE&md5=d3a5250f5cbd12b6cc1daaf1893a6f6cCoordinated Silencing of MYC-Mediated miR-29 by HDAC3 and EZH2 as a Therapeutic Target of Histone Modification in Aggressive B-Cell LymphomasZhang, Xinwei; Zhao, Xiaohong; Fiskus, Warren; Lin, Jianhong; Lwin, Tint; Rao, Rekha; Zhang, Yizhuo; Chan, John C.; Fu, Kai; Marquez, Victor E.; Chen-Kiang, Selina; Moscinski, Lynn C.; Seto, Edward; Dalton, William S.; Wright, Kenneth L.; Sotomayor, Eduardo; Bhalla, Kapil; Tao, JianguoCancer Cell (2012), 22 (4), 506-523CODEN: CCAECI; ISSN:1535-6108. (Elsevier Inc.)We investigated the transcriptional and epigenetic repression of miR-29 by MYC, HDAC3, and EZH2 in mantle cell lymphoma and other MYC-assocd. lymphomas. We demonstrate that miR-29 is repressed by MYC through a corepressor complex with HDAC3 and EZH2. MYC contributes to EZH2 upregulation via repression of the EZH2 targeting miR-26a, and EZH2 induces MYC via inhibition of the MYC targeting miR-494 to create pos. feedback. Combined inhibition of HDAC3 and EZH2 cooperatively disrupted the MYC-EZH2-miR-29 axis, resulting in restoration of miR-29 expression, downregulation of miR-29-targeted genes, and lymphoma growth suppression in vitro and in vivo. These findings define a MYC-mediated miRNA repression mechanism, shed light on MYC lymphomagenesis mechanisms, and reveal promising therapeutic targets for aggressive B-cell malignancies.
- 134Li, Y.; Kao, G. D.; Garcia, B. A.; Shabanowitz, J.; Hunt, D. F.; Qin, J.; Phelan, C.; Lazar, M. A. A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activity. Genes Dev. 2006, 20, 2566– 2579, DOI: 10.1101/gad.1455006[Crossref], [PubMed], [CAS], Google Scholar134https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtVamsr3J&md5=9abb518bd5f86ee9778ba9e0a724c8a9A novel histone deacetylase pathway regulates mitosis by modulating Aurora B kinase activityLi, Yun; Kao, Gary D.; Garcia, Benjamin A.; Shabanowitz, Jeffrey; Hunt, Donald F.; Qin, Jun; Phelan, Caroline; Lazar, Mitchell A.Genes & Development (2006), 20 (18), 2566-2579CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Histone deacetylase (HDAC) inhibitors perturb the cell cycle and have great potential as anti-cancer agents, but their mechanism of action is not well established. HDACs classically function as repressors of gene expression, tethered to sequence-specific transcription factors. Here we report that HDAC3 is a crit., transcription-independent regulator of mitosis. HDAC3 forms a complex with A-Kinase-Anchoring Proteins AKAP95 and HA95, which are targeted to mitotic chromosomes. Deacetylation of H3 in mitosis requires AKAP95/HA95 and HDAC3 and provides a hypoacetylated H3 tail that is the preferred substrate for Aurora B kinase. Phosphorylation of H3S10 by Aurora B leads to dissocn. of HP1 proteins from methylated H3K9 residues on mitotic heterochromatin. This transcription-independent pathway, involving interdependent changes in histone modification and protein assocn., is required for normal progression through mitosis and is an unexpected target of HDAC inhibitors, a class of drugs currently in clin. trials for treating cancer.
- 135Falkenberg, K. J.; Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discovery 2014, 13, 673– 691, DOI: 10.1038/nrd4360[Crossref], [PubMed], [CAS], Google Scholar135https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtlKrtLjI&md5=ccfb68fa3fd4685e2305cdf8a6a9c81aHistone deacetylases and their inhibitors in cancer, neurological diseases and immune disordersFalkenberg, Katrina J.; Johnstone, Ricky W.Nature Reviews Drug Discovery (2014), 13 (9), 673-691CODEN: NRDDAG; ISSN:1474-1776. (Nature Publishing Group)A review. Epigenetic aberrations, which are recognized as key drivers of several human diseases, are often caused by genetic defects that result in functional deregulation of epigenetic proteins, their altered expression and/or their atypical recruitment to certain gene promoters. Importantly, epigenetic changes are reversible, and epigenetic enzymes and regulatory proteins can be targeted using small mols. This Review discusses the role of altered expression and/or function of one class of epigenetic regulators - histone deacetylases (HDACs) - and their role in cancer, neurol. diseases and immune disorders. We highlight the development of small-mol. HDAC inhibitors and their use in the lab., in preclin. models and in the clinic.
- 136Minami, J.; Suzuki, R.; Mazitschek, R.; Gorgun, G.; Ghosh, B.; Cirstea, D.; Hu, Y.; Mimura, N.; Ohguchi, H.; Cottini, F.; Jakubikova, J.; Munshi, N. C.; Haggarty, S. J.; Richardson, P. G.; Hideshima, T.; Anderson, K. C. Histone deacetylase 3 as a novel therapeutic target in multiple myeloma. Leukemia 2014, 28, 680– 689, DOI: 10.1038/leu.2013.231[Crossref], [PubMed], [CAS], Google Scholar136https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWru7%252FK&md5=4ff22875205c892a7bc8c82e2aa4bdd0Histone deacetylase 3 as a novel therapeutic target in multiple myelomaMinami, J.; Suzuki, R.; Mazitschek, R.; Gorgun, G.; Ghosh, B.; Cirstea, D.; Hu, Y.; Mimura, N.; Ohguchi, H.; Cottini, F.; Jakubikova, J.; Munshi, N. C.; Haggarty, S. J.; Richardson, P. G.; Hideshima, T.; Anderson, K. C.Leukemia (2014), 28 (3), 680-689CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Histone deacetylases (HDACs) represent novel mol. targets for the treatment of various types of cancers, including multiple myeloma (MM). Many HDAC inhibitors have already shown remarkable antitumor activities in the preclin. setting; however, their clin. utility is limited because of unfavorable toxicities assocd. with their broad range HDAC inhibitory effects. Isoform-selective HDAC inhibition may allow for MM cytotoxicity without attendant side effects. In this study, we demonstrated that HDAC3 knockdown and a small-mol. HDAC3 inhibitor BG45 trigger significant MM cell growth inhibition via apoptosis, evidenced by caspase and poly (ADP-ribose) polymerase cleavage. Importantly, HDAC3 inhibition downregulates phosphorylation (tyrosine 705 and serine 727) of signal transducers and activators of transcription 3 (STAT3). Neither interleukin-6 nor bone marrow stromal cells overcome this inhibitory effect of HDAC3 inhibition on phospho-STAT3 and MM cell growth. Moreover, HDAC3 inhibition also triggers hyperacetylation of STAT3, suggesting crosstalk signaling between phosphorylation and acetylation of STAT3. Importantly, inhibition of HDAC3, but not HDAC1 or 2, significantly enhances bortezomib-induced cytotoxicity. Finally, we confirm that BG45 alone and in combination with bortezomib trigger significant tumor growth inhibition in vivo in a murine xenograft model of human MM. Our results indicate that HDAC3 represents a promising therapeutic target, and validate a prototype novel HDAC3 inhibitor BG45 in MM.
- 137Leus, N. G. J.; Zwinderman, M. R. H.; Dekker, F. J. Histone deacetylase 3 (HDAC3) as emerging drug target in NF-κB-mediated inflammation. Curr. Opin. Chem. Biol. 2016, 33, 160– 168, DOI: 10.1016/j.cbpa.2016.06.019[Crossref], [PubMed], [CAS], Google Scholar137https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsF2qt7bO&md5=32cad5b6e5fe7f0b23903b9a893d4809Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-κB-mediated inflammationLeus, Niek G. J; Zwinderman, Martijn R. H; Dekker, Frank J.Current Opinion in Chemical Biology (2016), 33 (), 160-168CODEN: COCBF4; ISSN:1367-5931. (Elsevier B.V.)Activation of inflammatory gene expression is regulated, among other factors, by post-translational modifications of histone proteins. The most investigated type of histone modifications is lysine acetylations. Histone deacetylases (HDACs) remove acetylations from lysines, thereby influencing (inflammatory) gene expression. Intriguingly, apart from histones, HDACs also target non-histone proteins. The nuclear factor κB (NF-κB) pathway is an important regulator in the expression of numerous inflammatory genes, and acetylation plays a crucial role in regulating its responses. Several studies have shed more light on the role of HDAC 1-3 in inflammation with a particular pro-inflammatory role for HDAC 3. Nevertheless, the HDAC-NF-κB interactions in inflammatory signalling have not been fully understood. An important challenge in targeting the regulatory role of HDACs in the NF-κB pathway is the development of highly potent small mols. that selectively target HDAC iso-enzymes. This review focuses on the role of HDAC 3 in (NF-κB-mediated) inflammation and NF-κB lysine acetylation. In addn., we address the application of frequently used small mol. HDAC inhibitors as an approach to attenuate inflammatory responses, and their potential as novel therapeutics. Finally, recent progress and future directions in medicinal chem. efforts aimed at HDAC 3-selective inhibitors are discussed.
- 138Angiolilli, C.; Kabala, P. A.; Grabiec, A. M.; Van Baarsen, I. M.; Ferguson, B. S.; García, S.; Malvar Fernandez, B.; McKinsey, T. A.; Tak, P. P.; Fossati, G.; Mascagni, P.; Baeten, D. L.; Reedquist, K. A. Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann. Rheum. Dis. 2017, 76, 277– 285, DOI: 10.1136/annrheumdis-2015-209064[Crossref], [PubMed], [CAS], Google Scholar138https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhsFaiurk%253D&md5=3ed3855cc03247206f63ba518b19f12bHistone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytesAngiolilli, Chiara; Kabala, Pawel A.; Grabiec, Aleksander M.; Van Baarsen, Iris M.; Ferguson, Bradley S.; Garcia, Samuel; Fernandez, Beatriz Malvar; McKinsey, Timothy A.; Tak, Paul P.; Fossati, Gianluca; Mascagni, Paolo; Baeten, Dominique L.; Reedquist, Kris A.Annals of the Rheumatic Diseases (2017), 76 (1), 277-285CODEN: ARDIAO; ISSN:0003-4967. (BMJ Publishing Group)Non-selective histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated anti-inflammatory properties in both in vitro and in vivo models of rheumatoid arthritis (RA). Here, we investigated the potential contribution of specific class I and class IIb HDACs to inflammatory gene expression in RA fibroblastlike synoviocytes (FLS). RA FLS were incubated with pan-HDACi (ITF2357, givinostat) or selective HDAC1/2i, HDAC3/6i, HDAC6i and HDAC8i. Alternatively, FLS were transfected with HDAC3, HDAC6 or interferon (IFN)- α/β receptor alpha chain (IFNAR1) siRNA. mRNA expression of interleukin (IL)-1β-inducible genes was measured by quant. PCR (qPCR) array and signalling pathway activation by immunoblotting and DNA-binding assays. HDAC3/6i, but not HDAC1/2i and HDAC8i, significantly suppressed the majority of IL-1β-inducible genes targeted by pan-HDACi in RA FLS. Silencing of HDAC3 expression reproduced the effects of HDAC3/6i on gene regulation, contrary to HDAC6-specific inhibition and HDAC6 silencing. Screening of the candidate signal transducers and activators of transcription (STAT)1 transcription factor revealed that HDAC3/6i abrogated STAT1 Tyr701 phosphorylation and DNA binding, but did not affect STAT1 acetylation. HDAC3 activity was required for type I IFN prodn. and subsequent STAT1 activation in FLS. Suppression of type I IFN release by HDAC3/6i resulted in reduced expression of a subset of IFN-dependent genes, including the chemokines CXCL9 and CXCL11. Inhibition of HDAC3 in RA FLS largely recapitulates the effects of pan-HDACi in suppressing inflammatory gene expression, including type I IFN prodn. in RA FLS. Our results identify HDAC3 as a potential therapeutic target in the treatment of RA and type I IFN-driven autoimmune diseases.
- 139Weïwer, M.; Lewis, M. C.; Wagner, F. F.; Holson, E. B. Therapeutic potential of isoform selective HDAC inhibitors for the treatment of schizophrenia. Future Med. Chem. 2013, 5, 1491– 1508, DOI: 10.4155/fmc.13.141[Crossref], [PubMed], [CAS], Google Scholar139https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsVWrsrvF&md5=64ccc93601eb4b9f1321bd4f8fa6258cTherapeutic potential of isoform selective HDAC inhibitors for the treatment of schizophreniaWeiwer, Michel; Lewis, Michael C.; Wagner, Florence F.; Holson, Edward B.Future Medicinal Chemistry (2013), 5 (13), 1491-1508CODEN: FMCUA7; ISSN:1756-8919. (Future Science Ltd.)A review. Increasing evidence supports a role for epigenetic involvement in some of the neurobiol. alterations obsd. in neurodegenerative and psychiatric disorders including schizophrenia. In particular, there is mounting evidence implicating dysfunction in acetylation status, a chromatin modification mediated in part by HDACs, as a possible contributing factor to certain facets of this debilitating disease. Addnl. data support the notion that small mol. inhibition of HDACs may provide therapeutic alternatives to treating many of the symptoms assocd. with schizophrenia, particularly cognitive deficits. However, the development of highly potent and selective inhibitors of the individual HDAC isoforms will be necessary to delineate the assocd. biol. effects and test the feasibility of such an approach for this complex and chronically treated disease. Here, we summarize current evidence for the role of HDAC isoforms in schizophrenia and highlight the state of the art in developing selective inhibitors of these isoforms as a potential treatment for schizophrenia.
- 140Kuboyama, T.; Wahane, S.; Huang, Y.; Zhou, X.; Wong, J. K.; Koemeter-Cox, A.; Martini, M.; Friedel, R. H.; Zou, H. HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. Sci. Rep. 2017, 7, 8641, DOI: 10.1038/s41598-017-08535-4[Crossref], [PubMed], [CAS], Google Scholar140https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cfpsVKqug%253D%253D&md5=59b8a9bfa8a91042ea92866073a6f6a4HDAC3 inhibition ameliorates spinal cord injury by immunomodulationKuboyama Tomoharu; Wahane Shalaka; Huang Yong; Zhou Xiang; Wong Jamie K; Koemeter-Cox Andrew; Martini Michael; Friedel Roland H; Zou Hongyan; Kuboyama Tomoharu; Wong Jamie K; Koemeter-Cox Andrew; Friedel Roland H; Zou HongyanScientific reports (2017), 7 (1), 8641 ISSN:.Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.
- 141Chen, S.; Ye, J.; Chen, X.; Shi, J.; Wu, W.; Lin, W.; Lin, W.; Li, Y.; Fu, H.; Li, S. Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3. J. Neuroinflammation 2018, 15, 150, DOI: 10.1186/s12974-018-1193-6[Crossref], [PubMed], [CAS], Google Scholar141https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWgur%252FP&md5=18c51bab4fe7872913cc9e9285cc0e5eValproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-κB pathway dependent of HDAC3Chen, Shoubo; Ye, Jingfang; Chen, Xiangrong; Shi, Jinnan; Wu, Wenhua; Lin, Wenping; Lin, Weibin; Li, Yasong; Fu, Huangde; Li, ShunJournal of Neuroinflammation (2018), 15 (), 150/1-150/14CODEN: JNOEB3; ISSN:1742-2094. (BioMed Central Ltd.)Background: Microglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF- κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential mol. mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment. Methods: The Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to det. the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot anal. were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI. Results: The results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI. Conclusions: These results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.
- 142Kwapis, J. L.; Alaghband, Y.; Kramár, E. A.; López, A. J.; Vogel Ciernia, A.; White, A. O.; Shu, G.; Rhee, D.; Michael, C. M.; Montellier, E.; Liu, Y.; Magnan, C. N.; Chen, S.; Sassone-Corsi, P.; Baldi, P.; Matheos, D. P.; Wood, M. A. Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory. Nat. Commun. 2018, 9, 3323, DOI: 10.1038/s41467-018-05868-0[Crossref], [PubMed], [CAS], Google Scholar142https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3c3gtVOjug%253D%253D&md5=1a2b79c97f7108ddfef8a25ed31e50c7Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memoryKwapis Janine L; Alaghband Yasaman; Kramar Eniko A; Lopez Alberto J; Shu Guanhua; Rhee Diane; Michael Christina M; Matheos Dina P; Wood Marcelo A; Kwapis Janine L; Alaghband Yasaman; Kramar Eniko A; Lopez Alberto J; Shu Guanhua; Rhee Diane; Michael Christina M; Matheos Dina P; Wood Marcelo A; Kwapis Janine L; Wood Marcelo A; Vogel Ciernia Annie; White Andre O; Montellier Emilie; Sassone-Corsi Paolo; Liu Yu; Magnan Christophe N; Chen Siwei; Baldi Pierre; Liu Yu; Magnan Christophe N; Chen Siwei; Baldi PierreNature communications (2018), 9 (1), 3323 ISSN:.Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and experience-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.
- 143Kuta, R.; Larochelle, N.; Fernandez, M.; Pal, A.; Minotti, S.; Tibshirani, M.; St. Louis, K.; Gentil, B. J.; Nalbantoglu, J. N.; Hermann, A.; Durham, H. D. Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models. Cell Stress Chaperones 2020, 25, 173– 191, DOI: 10.1007/s12192-019-01064-1[Crossref], [PubMed], [CAS], Google Scholar143https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXmtVyqsQ%253D%253D&md5=6027a7e2f074f7935a2fca9062b317d9Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS modelsKuta, Rachel; Larochelle, Nancy; Fernandez, Mario; Pal, Arun; Minotti, Sandra; Tibshirani, Michael; St. Louis, Kyle; Gentil, Benoit J.; Nalbantoglu, Josephine N.; Hermann, Andreas; Durham, Heather D.Cell Stress & Chaperones (2020), 25 (1), 173-191CODEN: CSCHFG; ISSN:1355-8145. (Springer)Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSP525Lmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.
- 144Nghia, N. A.; Hirasawa, T.; Kasai, H.; Obata, C.; Moriishi, K.; Mochizuki, K.; Koizumi, S.; Kubota, T. Long-term imipramine treatment increases N-methyl-d-aspartate receptor activity and expression via epigenetic mechanisms. Eur. J. Pharmacol. 2015, 752, 69– 77, DOI: 10.1016/j.ejphar.2015.02.010[Crossref], [PubMed], [CAS], Google Scholar144https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXjt1arur8%253D&md5=32fa23fb10469f6c5093f04bcd727d76Long-term imipramine treatment increases N-methyl-D-aspartate receptor activity and expression via epigenetic mechanismsNghia, Nguyen An; Hirasawa, Takae; Kasai, Hirotake; Obata, Chie; Moriishi, Kohji; Mochizuki, Kazuki; Koizumi, Schuichi; Kubota, TakeoEuropean Journal of Pharmacology (2015), 752 (), 69-77CODEN: EJPHAZ; ISSN:0014-2999. (Elsevier B.V.)Imipramine, a major antidepressant, is known to inhibit reuptake of serotonin and norepinephrine, which contributes to recovery from major depressive disorder. It has recently been reported that acute imipramine treatment inhibits N-methyl-D-aspartate (NMDA) receptor activity. However, the mechanisms underlying long-term effects of imipramine have not been identified. We tested these distinct effects in mouse cortical neurons and found that acute (30 s) imipramine treatment decreased Ca2+ influx through NMDA receptors, whereas long-term treatment (48 h) increased Ca2+ influx via the same receptors. Furthermore, long-term treatment increased NMDA receptor 2B (NR2B) subunit expression via epigenetic changes, including increased acetylation of histones H3K9 and H3K27 in the NR2B promoter and decreased activity of histone deacetylase 3 (HDAC3) and HDAC4. These results suggest that the long-term effects of imipramine on NMDA receptors are quite different from its acute effects. Furthermore, increased NR2B expression via epigenetic alterations might be a part of the mechanism responsible for this long-term effect.
- 145Venkatraman, A.; Hu, Y. S.; Didonna, A.; Cvetanovic, M.; Krbanjevic, A.; Bilesimo, P.; Opal, P. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1. Hum. Mol. Genet. 2014, 23, 3733– 3745, DOI: 10.1093/hmg/ddu081[Crossref], [PubMed], [CAS], Google Scholar145https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhtVentLjO&md5=3ed40191561c696b23873f49095f53a2The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1Venkatraman, Anand; Hu, Yuan-Shih; Didonna, Alessandro; Cvetanovic, Marija; Krbanjevic, Aleksandar; Bilesimo, Patrice; Opal, PuneetHuman Molecular Genetics (2014), 23 (14), 3733-3745CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease caused by a pathogenic glutamine repeat expansion in the protein ataxin-1 (ATXN1). One likely mechanism mediating pathogenesis is excessive transcriptional repression induced by the expanded ATXN-1. Because ATXN1 binds HDAC3, a Class I histone deacetylase (HDAC) that we have found to be required for ATXN1-induced transcriptional repression, we tested whether genetically depleting HDAC3 improves the phenotype of the SCA1 knock-in mouse (SCA1154Q/2Q), the most physiol. relevant model of SCA1. Given that HDAC3 null mice are embryonic lethal, we used for our analyses a combination of HDAC3 haploinsufficient and Purkinje cell (PC)-specific HDAC3 null mice. Although deleting a single allele of HDAC3 in the context of SCA1 was insufficient to improve cerebellar and cognitive deficits of the disease, a complete loss of PC HDAC3 was highly deleterious both behaviorally, with mice showing early onset ataxia, and pathol., with progressive histol. evidence of degeneration. Inhibition of HDAC3 may yet have a role in SCA1 therapy, but our study provides cautionary evidence that this approach could produce untoward effects. Indeed, the neurotoxic consequences of HDAC3 depletion could prove relevant, wherever pharmacol. inhibition of HDAC3 is being contemplated, in disorders ranging from cancer to neurodegeneration.
- 146Choi, H. K.; Choi, Y.; Kang, H.; Lim, E. J.; Park, S. Y.; Lee, H. S.; Park, J. M.; Moon, J.; Kim, Y. J.; Choi, I.; Joe, E. H.; Choi, K. C.; Yoon, H. G. PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death. Hum. Mol. Genet. 2015, 24, 1127– 1141, DOI: 10.1093/hmg/ddu526[Crossref], [PubMed], [CAS], Google Scholar146https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVylsL3P&md5=078a2d9bff16f9aebb0b4189830c040fPINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell deathChoi, Hyo-Kyoung; Choi, Youngsok; Kang, Hee Bum; Lim, Eun-jin; Park, Soo-Yeon; Lee, Hyun-Seob; Park, Ji-Min; Moon, Jisook; Kim, Yoon-Jung; Choi, Insup; Joe, Eun-Hye; Choi, Kyung-Chul; Yoon, Ho-GeunHuman Molecular Genetics (2015), 24 (4), 1127-1141CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)Deciphering the mol. basis of neuronal cell death is a central issue in the etiol. of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the mol. basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct assocn. with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3S424E substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.
- 147Bardai, F. H.; Verma, P.; Smith, C.; Rawat, V.; Wang, L.; D’Mello, S. R. Disassociation of histone deacetylase-3 from normal huntingtin underlies mutant huntingtin neurotoxicity. J. Neurosci. 2013, 33, 11833– 11838, DOI: 10.1523/JNEUROSCI.5831-12.2013[Crossref], [PubMed], [CAS], Google Scholar147https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtFKqu77F&md5=f5d39b1df5ef060d99bf39d9bdb28a2cDisassociation of histone deacetylase-3 from normal Huntingtin underlies mutant huntingtin neurotoxicityBardai, Farah H.; Verma, Pragya; Smith, Chad; Rawat, Varun; Wang, Lulu; D'Mello, Santosh R.Journal of Neuroscience (2013), 33 (29), 11833-11838CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Huntington's disease (HD) is caused by a polyglutamine expansion within the huntingtin (Htt) protein. Both loss of function of normal Htt and gain of a toxic function by the polyglutamine-expanded mutant Htt protein have been proposed to be responsible for HD, although the mol. mechanisms involved are unclear. We show that Htt is a neuroprotective protein in both HD-related and unrelated model systems. Neuroprotection by Htt is mediated by its sequestration of histone deacetylase-3 (HDAC3), a protein known to promote neuronal death. In contrast to the normal Htt, mutant Htt interacts poorly with HDAC3. However, expression of mutant Htt liberates HDAC3 from Htt, thus de-repressing its neurotoxic activity. Indeed, mutant Htt neurotoxicity is inhibited by the knockdown of HDAC3 and markedly reduced in HDAC3-deficient neurons. A redn. in Htt-HDAC3 interaction is also seen in neurons exposed to other apoptotic stimuli and in the striatum of R6/2 HD mice. Our results suggest that the robust interaction between Htt and HDAC3 along with the ability of mutant Htt to disrupt this assocn. while not itself interacting with HDAC3 provides an explanation for both the loss-of-function and gain-of-toxic-function mechanisms proposed for HD. Moreover, our results identify HDAC3 as an essential player in mutant Htt-induced neurodegeneration.
- 148Jia, H.; Pallos, J.; Jacques, V.; Lau, A.; Tang, B.; Cooper, A.; Syed, A.; Purcell, J.; Chen, Y.; Sharma, S.; Sangrey, G. R.; Darnell, S. B.; Plasterer, H.; Sadri-Vakili, G.; Gottesfeld, J. M.; Thompson, L. M.; Rusche, J. R.; Marsh, J. L.; Thomas, E. A. Histone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine elicited phenotypes in model systems of Huntington’s disease. Neurobiol. Dis. 2012, 46, 351– 361, DOI: 10.1016/j.nbd.2012.01.016[Crossref], [PubMed], [CAS], Google Scholar148https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xltlagu7w%253D&md5=eb0b2461d8059ed525e3c477db32430dHistone deacetylase (HDAC) inhibitors targeting HDAC3 and HDAC1 ameliorate polyglutamine-elicited phenotypes in model systems of Huntington's diseaseJia, Haiqun; Pallos, Judit; Jacques, Vincent; Lau, Alice; Tang, Bin; Cooper, Andrew; Syed, Adeela; Purcell, Judith; Chen, Yi; Sharma, Shefali; Sangrey, Gavin R.; Darnell, Shayna B.; Plasterer, Heather; Sadri-Vakili, Ghazaleh; Gottesfeld, Joel M.; Thompson, Leslie M.; Rusche, James R.; Marsh, J. Lawrence; Thomas, Elizabeth A.Neurobiology of Disease (2012), 46 (2), 351-361CODEN: NUDIEM; ISSN:0969-9961. (Elsevier Inc.)We have previously demonstrated amelioration of Huntington's disease (HD)-related phenotypes in R6/2 transgenic mice in response to treatment with the novel histone deacetylase (HDAC) inhibitor 4b. Here we have measured the selectivity profiles of 4b and related compds. against class I and class II HDACs and have tested their ability to restore altered expression of genes related to HD pathol. in mice and to rescue disease effects in cell culture and Drosophila models of HD. R6/2 transgenic and wild-type (wt) mice received daily injections of HDAC inhibitors for 3 days followed by real-time PCR anal. to detect expression differences for 13 HD-related genes. We find that HDACi 4b and 136, two compds. showing high potency for inhibiting HDAC3 were most effective in reversing the expression of genes relevant to HD, including Ppp1r1b, which encodes DARPP-32, a marker for medium spiny striatal neurons. In contrast, compds. targeting HDAC1 were less effective at correcting gene expression abnormalities in R6/2 transgenic mice, but did cause significant increases in the expression of selected genes. An addnl. panel of 4b-related compds. was tested in a Drosophila model of HD and in STHdh Q111 striatal cells to further distinguish HDAC selectivity. Significant improvement in huntingtin-elicited Drosophila eye neurodegeneration in the fly was obsd. in response to treatment with compds. targeting human HDAC1 and/or HDAC3. In STHdh Q111 striatal cells, the ability of HDAC inhibitors to improve huntingtin-elicited metabolic deficits correlated with the potency at inhibiting HDAC1 and HDAC3, although the IC50 values for HDAC1 inhibition were typically 10-fold higher than for inhibition of HDAC3. Assessment of HDAC protein localization in brain tissue by Western blot anal. revealed accumulation of HDAC1 and HDAC3 in the nucleus of HD transgenic mice compared to wt mice, with a concurrent decrease in cytoplasmic localization, suggesting that these HDACs contribute to a repressive chromatin environment in HD. No differences were detected in the localization of HDAC2, HDAC4 or HDAC7. These results suggest that inhibition of HDACs 1 and 3 can relieve HD-like phenotypes in model systems and that HDAC inhibitors targeting these isotypes might show therapeutic benefit in human HD.
- 149Janczura, K. J.; Volmar, C. H.; Sartor, G. C.; Rao, S. J.; Ricciardi, N. R.; Lambert, G.; Brothers, S. P.; Wahlestedt, C. Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model. Proc. Natl. Acad. Sci. U. S. A. 2018, 115, E11148– E11157, DOI: 10.1073/pnas.1805436115[Crossref], [PubMed], [CAS], Google Scholar149https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit1CrtrrP&md5=f36c313cbc1bb2c7dc7cc1590351cb18Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse modelJanczura, Karolina J.; Volmar, Claude-Henry; Sartor, Gregory C.; Rao, Sunil J.; Ricciardi, Natalie R.; Lambert, Guerline; Brothers, Shaun P.; Wahlestedt, ClaesProceedings of the National Academy of Sciences of the United States of America (2018), 115 (47), E11148-E11157CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Alzheimer's disease (AD) the leading cause of age-related dementia. Neuropathol. hallmarks of AD include brain deposition of β-amyloid plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-assocd. sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1-42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathol. tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1-42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1-42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEe4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins assocd. with AD pathophysiol., supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
- 150Zhu, X.; Wang, S.; Yu, L.; Jin, J.; Ye, X.; Liu, Y.; Xu, Y. HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer’s disease. Aging Cell 2017, 16, 1073– 1082, DOI: 10.1111/acel.12642[Crossref], [PubMed], [CAS], Google Scholar150https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1OhsrzN&md5=46f797519fd4f22e253f3decf83fe8ecHDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's diseaseZhu, Xiaolei; Wang, Sulei; Yu, Linjie; Jin, Jiali; Ye, Xing; Liu, Yi; Xu, YunAging Cell (2017), 16 (5), 1073-1082CODEN: ACGECQ; ISSN:1474-9718. (Wiley-Blackwell)Summary : The accumulation and deposition of beta-amyloid (Aβ) is a key neuropathol. hallmark of Alzheimer's disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms assocd. with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6- and 9-mo-old APPswe/PS1dE9 (APP/PS1) mice compared with that in age-matched wild-type C57BL/6 (B6) mice. Lentivirus -mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine d., glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine d. is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9-mo-old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine d. in 6-mo-old APP/PS1 mice. In conclusion, our results indicate that HDAC3 neg. regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.
- 151Lee, H. A.; Lee, D. Y.; Cho, H. M.; Kim, S. Y.; Iwasaki, Y.; Kim, I. K. Histone deacetylase inhibition attenuates transcriptional activity of mineralocorticoid receptor through its acetylation and prevents development of hypertension. Circ. Res. 2013, 112, 1004– 1012, DOI: 10.1161/CIRCRESAHA.113.301071[Crossref], [PubMed], [CAS], Google Scholar151https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkvVKjtbo%253D&md5=a4b417602f9ce64414c642b83ea661c9Histone Deacetylase Inhibition Attenuates Transcriptional Activity of Mineralocorticoid Receptor Through Its Acetylation and Prevents Development of HypertensionLee, Hae-Ahm; Lee, Dong-Youb; Cho, Hyun-Min; Kim, Sang-Yeob; Iwasaki, Yasumasa; Kim, In KyeomCirculation Research (2013), 112 (7), 1004-1012CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Inhibition of histone deacetylases (HDACs) results in attenuated development of hypertension in deoxycorticosterone acetate-induced hypertensive rats and spontaneously hypertensive rats. However, the mol. mechanism remains elusive. Objective: We hypothesized that HDAC inhibition attenuates transcriptional activity of mineralocorticoid receptor (MR) through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats. Methods and results: Expression of MR target genes was measured by quant. real-time polymerase chain reaction. Recruitment of MR and RNA polymerase II on promoters of target genes was analyzed by chromatin immunopptn. assay. Live cell imaging was performed for visualization of nuclear translocation of MR. MR acetylation was detd. by Western blot with anti-acetyl-lysine antibody after immunopptn. with anti-MR antibody. Transcriptional activity of MR was detd. by luciferase assay. For establishment of a hyperaldosteronism animal, Sprague-Dawley rats underwent uninephrectomy and received s.c. injection of 40 mg/kg per wk of deoxycorticosterone acetate and drinking water contg. 1% NaCl. Treatment with a HDAC class I inhibitor resulted in reduced expression of MR target genes in accordance with reduced recruitment of MR and RNA polymerase II on promoters of target genes. HDAC inhibition promoted MR acetylation, leading to decreased transcriptional activity of MR. Knockdown or inhibition of HDAC3 resulted in reduced expression of MR target genes induced by mineralocorticoids. Conclusions: These results indicate that HDAC inhibition attenuates transcriptional activity of MR through its acetylation and prevents development of hypertension in deoxycorticosterone acetate-induced hypertensive rats.
- 152Nozik-Grayck, E.; Woods, C.; Stearman, R. S.; Venkataraman, S.; Ferguson, B. S.; Swain, K.; Bowler, R. P.; Geraci, M. W.; Ihida-Stansbury, K.; Stenmark, K. R.; McKinsey, T. A.; Domann, F. E. Histone deacetylation contributes to low extracellular superoxide dismutase expression in human idiopathic pulmonary arterial hypertension. Am. J. Physiol. Lung Cell Mol. Physiol. 2016, 311, L124– L1234, DOI: 10.1152/ajplung.00263.2015
- 153Zampetaki, A.; Zeng, L.; Margariti, A.; Xiao, Q.; Li, H.; Zhang, Z.; Pepe, A. E.; Wang, G.; Habi, O.; deFalco, E.; Cockerill, G.; Mason, J. C.; Hu, Y.; Xu, Q. Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow. Circulation 2010, 121, 132– 142, DOI: 10.1161/CIRCULATIONAHA.109.890491[Crossref], [PubMed], [CAS], Google Scholar153https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhs1WjtrjF&md5=1d871191f2a860279e21de80bce243ddHistone Deacetylase 3 Is Critical in Endothelial Survival and Atherosclerosis Development in Response to Disturbed FlowZampetaki, Anna; Zeng, Lingfang; Margariti, Andriana; Xiao, Qingzhong; Li, Hongling; Zhang, Zhongyi; Pepe, Anna Elena; Wang, Gang; Habi, Ouassila; de Falco, Elena; Cockerill, Gillian; Mason, Justin C.; Hu, Yanhua; Xu, QingboCirculation (2010), 121 (1), 132-142CODEN: CIRCAZ; ISSN:0009-7322. (Lippincott Williams & Wilkins)Background-Histone deacetylase 3 (HDAC3) is known to play a crucial role in the differentiation of endothelial progenitors. The role of HDAC3 in mature endothelial cells, however, is not well understood. Here, we investigated the function of HDAC3 in preserving endothelial integrity in areas of disturbed blood flow, ie, bifurcation areas prone to atherosclerosis development. Methods and Results-En face staining of aortas from apolipoprotein E-knockout mice revealed increased expression of HDAC3, specifically in these branching areas in vivo, whereas rapid upregulation of HDAC3 protein was obsd. in endothelial cells exposed to disturbed flow in vitro. Interestingly, phosphorylation of HDAC3 at serine/threonine was obsd. in these cells, suggesting that disturbed flow leads to posttranscriptional modification and stabilization of the HDAC3 protein. Coimmunopptn. expts. showed that HDAC3 and Akt form a complex. Using a series of constructs harboring deletions, we found residues 136 to 206 of HDAC3 to be crucial in this interaction. Enforced expression of HDAC3 resulted in increased phosphorylation of Akt and upregulation of its kinase activity. In line with these findings, knockdown of HDAC3 with lentiviral vectors (shHDAC3) led to a dramatic decrease in cell survival accompanied by apoptosis in endothelial cells. In aortic isografts of apolipoprotein E-knockout mice treated with shHDAC3, a robust atherosclerotic lesion was formed. Surprisingly, 3 of the 8 mice that received shHDAC3-infected grafts died within 2 days after the operation. Miller staining of the isografts revealed disruption of the basement membrane and rupture of the vessel. Conclusions-Our findings demonstrated that HDAC3 serves as an essential prosurvival mol. with a crit. role in maintaining the endothelial integrity via Akt activation and that severe atherosclerosis and vessel rupture in isografted vessels of apolipoprotein E-knockout mice occur when HDAC3 is knocked down.
- 154Dirice, E.; Ng, R.; Martinez, R.; Hu, J.; Wagner, F. F.; Holson, E. B.; Wagner, B. K.; Kulkarni, R. N. Isoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetes. J. Biol. Chem. 2017, 292, 17598– 17608, DOI: 10.1074/jbc.M117.804328[Crossref], [PubMed], [CAS], Google Scholar154https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhslehsrfI&md5=b05649e9b132289bd49ad76398f6615cIsoform-selective inhibitor of histone deacetylase 3 (HDAC3) limits pancreatic islet infiltration and protects female nonobese diabetic mice from diabetesDirice, Ercument; Ng, Raymond W. S.; Martinez, Rachael; Hu, Jiang; Wagner, Florence F.; Holson, Edward B.; Wagner, Bridget K.; Kulkarni, Rohit N.Journal of Biological Chemistry (2017), 292 (43), 17598-17608CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Preservation of insulin-secreting β-cells is an important goal for therapies aimed at restoring normoglycemia in patients with diabetes. One approach, the inhibition of histone deacetylases (HDACs), has been reported to suppress pancreatic islet inflammation and β-cell apoptosis in vitro. In this report, we demonstrate the efficacy of HDAC inhibitors (HDACi) in vivo. We show that daily administration of BRD3308, an isoform-selective HDAC3 inhibitor, for 2 wk to female nonobese diabetic (NOD) mice, beginning at 3 wk of age, followed by twice-weekly injections until age 25 wk, protects the animals from diabetes. The preservation of β-cells was because of a significant decrease in islet infiltration of mononuclear cells. Moreover, the BRD3308 treatment increased basal insulin secretion from islets cultured in vitro. All metabolic tissues tested in vehicle- or BRD3308-treated groups showed virtually no sign of immune cell infiltration, except minimal infiltration in white adipose tissue in animals treated with the highest BRD3308 dose (10 mg/kg), providing addnl. evidence of protection from immune attack in the treated groups. Furthermore, pancreata from animals treated with 10 mg/kg BRD3308 exhibited significantly decreased nos. of apoptotic β-cells compared with those treated with vehicle or low-dose BRD3308. Finally, animals treated with 1 or 10 mg/kg BRD3308 had enhanced β-cell proliferation. These in vivo results point to the potential use of selective HDAC3 inhibitors as a therapeutic approach to suppress pancreatic islet infiltration and prevent β-cell death with the long-term goal of limiting the progression of type 1 diabetes.
- 155Meier, B. C.; Wagner, B. K. Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. Epigenomics 2014, 6, 209– 214, DOI: 10.2217/epi.14.11[Crossref], [PubMed], [CAS], Google Scholar155https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXnslClt7g%253D&md5=e6342f84c653e4d32e272e736789e2b1Inhibition of HDAC3 as a strategy for developing novel diabetes therapeuticsMeier, Bennett C.; Wagner, Bridget K.Epigenomics (2014), 6 (2), 209-214CODEN: EPIGC7; ISSN:1750-192X. (Future Medicine Ltd.)A review. Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. Recent studies have put a greater spotlight on metabolic diseases, in particular Type 1 and Type 2 diabetes, as potential indications for which HDAC inhibition could be beneficial. Evidence suggests that inhibition of HDAC3 protects β-cells from cytokine-induced apoptosis, an important event in the development of Type 1 diabetes. On the other hand, the pathogenesis of Type 2 diabetes involves a combination of peripheral insulin resistance and pancreatic β-cell failure. Again, data from the literature indicate that HDAC3 regulates genes involved in key metabolic events. Together, these results suggest that selective inhibition of HDAC3 may be an attractive strategy for targeting these diseases.
- 156Chen, W. B.; Gao, L.; Wang, J.; Wang, Y. G.; Dong, Z.; Zhao, J.; Mi, Q. S.; Zhou, L. Conditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetes. Oncotarget 2016, 7, 57485– 57497, DOI: 10.18632/oncotarget.11295[Crossref], [PubMed], [CAS], Google Scholar156https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2szitFKluw%253D%253D&md5=4d3ed8a674b52a02db968b6420ce0dffConditional ablation of HDAC3 in islet beta cells results in glucose intolerance and enhanced susceptibility to STZ-induced diabetesChen Wen-Bin; Wang Jie; Mi Qing-Sheng; Zhou Li; Chen Wen-Bin; Gao Ling; Chen Wen-Bin; Wang Jie; Mi Qing-Sheng; Zhou Li; Wang Jie; Wang Yan-Gang; Dong Zheng; Zhao Jiajun; Mi Qing-Sheng; Zhou LiOncotarget (2016), 7 (36), 57485-57497 ISSN:.Histone deacetylases (HDACs) are enzymes that regulate gene expression by modifying chromatin structure through removal of acetyl groups from target histones or non-histone proteins. Previous in vitro studies suggest that HDACs may be novel pharmacological targets in immune-mediated islet β-cell destruction. However, the role of specific HDAC in islet β-cell development and function remain unclear. Here, we generated a conditional islet β-cells specific HDAC3 deletion mouse model to determine the consequences of HDAC3 depletion on islet β-cell differentiation, maintenance and function. Islet morphology, insulin secretion, glucose tolerance, and multiple low-dose streptozotocin (STZ)-induced diabetes incidence were evaluated and compared between HDAC3 knockout and wild type littermate controls. Mice with β-cell-specific HDAC3 deletion displayed decreased pancreatic insulin content, disrupted glucose-stimulated insulin secretion, with intermittent spontaneous diabetes and dramatically enhanced susceptibility to STZ-induced diabetes. Furthermore, islet β-cell line, MIN6 cells with siRNA-mediated HDAC3 silence, showed decreased insulin gene transcription, which was mediated, at least partially, through the upregulation of suppressors of cytokine signaling 3 (SOCS3). These results indicate the critical role of HDAC3 in normal β-cell differentiation, maintenance and function.
- 157Maubon, D.; Bougdour, A.; Wong, Y. S.; Brenier-Pinchart, M. P.; Curt, A.; Hakimi, M. A.; Pelloux, H. Activity of histone deacetylase inhibitor FR235222 on Taxoplasma gonidii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. Antimicrob. Agents Chemother. 2010, 54, 4843– 4850, DOI: 10.1128/AAC.00462-10[Crossref], [PubMed], [CAS], Google Scholar157https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhsVCitrrF&md5=9cac7e307f59c9bbb90ac01985540648Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compoundsMaubon, Daniele; Bougdour, Alexandre; Wong, Yung-Sing; Brenier-Pinchart, Marie-Pierre; Curt, Aurelie; Hakimi, Mohamed-Ali; Pelloux, HerveAntimicrobial Agents and Chemotherapy (2010), 54 (11), 4843-4850CODEN: AMACCQ; ISSN:0066-4804. (American Society for Microbiology)Bradyzoite-to-tachyzoite conversion plays a role in the pathogenesis of recrudescence of ocular toxoplasmosis and disease in immunocompromised persons. The currently available medicines are ineffective on cysts and fail to prevent reactivation of latent toxoplasmosis. A previous study showed that the histone deacetylase inhibitor FR235222 has a dramatic effect on tachyzoite growth and induces tachyzoite-to-bradyzoite conversion in vitro. The present study shows that FR235222 can target in vitro-converted cysts and bradyzoites. Moreover, the compd. is active on ex vivo T. gondii cysts. Free bradyzoites isolated after lysis of the cell wall did not proliferate in vitro when the cyst was treated with FR235222. The results imply that this compd. is able to cross the T. gondii cystic cell wall. Fluorescent labeling shows that the compd. impairs the capacity of the bradyzoites to convert without damaging the cyst wall integrity. In vivo inoculation of formerly treated cysts fails to infect mice when these cysts were treated with FR235222. We used our structural knowledge of FR235222 and its target, T. gondii HDAC3, to synthesize new FR235222 deriv. compds. We identified two new mols. that are highly active against tachyzoites. They harbor a better selectivity index that is more suitable for a future in vivo approach. These results identify FR235222 and its derivs. as new lead compds. in the range of therapeutics available for acute and chronic toxoplasmosis.
- 158Farhat, D. C.; Swale, C.; Dard, C.; Cannella, D.; Ortet, P.; Barakat, M.; Sindikubwabo, F.; Belmudes, L.; De Bock, P. J.; Couté, Y.; Bougdour, A.; Hakimi, M. A. A MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitment. Nat. Microbiol. 2020, 5, 570– 583, DOI: 10.1038/s41564-020-0674-4[Crossref], [PubMed], [CAS], Google Scholar158https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXjvFyitLc%253D&md5=66b293770e5c3857bec274fa06266fafA MORC-driven transcriptional switch controls Toxoplasma developmental trajectories and sexual commitmentFarhat, Dayana C.; Swale, Christopher; Dard, Celine; Cannella, Dominique; Ortet, Philippe; Barakat, Mohamed; Sindikubwabo, Fabien; Belmudes, Lucid; De Bock, Pieter-Jan; Coute, Yohann; Bougdour, Alexandre; Hakimi, Mohamed-AliNature Microbiology (2020), 5 (4), 570-583CODEN: NMAICH; ISSN:2058-5276. (Nature Research)Abstr.: Toxoplasma gondii has a complex life cycle that is typified by asexual development that takes place in vertebrates, and sexual reprodn., which occurs exclusively in felids and is therefore less studied. The developmental transitions rely on changes in the patterns of gene expression, and recent studies have assigned roles for chromatin shapers, including histone modifications, in establishing specific epigenetic programs for each given stage. Here, we identified the T. gondii microrchidia (MORC) protein as an upstream transcriptional repressor of sexual commitment. MORC, in a complex with Apetala 2 (AP2) transcription factors, was shown to recruit the histone deacetylase HDAC3, thereby impeding the accessibility of chromatin at the genes that are exclusively expressed during sexual stages. We found that MORC-depleted cells underwent marked transcriptional changes, resulting in the expression of a specific repertoire of genes, and revealing a shift from asexual proliferation to sexual differentiation. MORC acts as a master regulator that directs the hierarchical expression of secondary AP2 transcription factors, and these transcription factors potentially contribute to the unidirectionality of the life cycle. Thus, MORC plays a cardinal role in the T. gondii life cycle, and its conditional depletion offers a method to study the sexual development of the parasite in vitro, and is proposed as an alternative to the requirement of T. gondii infections in cats.
- 159Huber, K.; Doyon, G.; Plaks, J.; Fyne, E.; Mellors, J. W.; Sluis-Cremer, N. Inhibitors of histone deacetylases correlation between isoform specificity and reactivation of type 1 (HIV-1) from latently infected cells. J. Biol. Chem. 2011, 286, 22211– 22218, DOI: 10.1074/jbc.M110.180224[Crossref], [PubMed], [CAS], Google Scholar159https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXns1Kks7Y%253D&md5=1d62cae8ca4609975bb0082ce17fd73bInhibitors of Histone Deacetylases: Correlation Between Isoform Specificity and Reactivation of HIV Type 1 (HIV-1) From Latently Infected CellsHuber, Kelly; Doyon, Genevieve; Plaks, Joseph; Fyne, Elizabeth; Mellors, John W.; Sluis-Cremer, NicolasJournal of Biological Chemistry (2011), 286 (25), 22211-22218CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chem. approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunopptn. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC50 = 5.5 mM) relative to HDAC1 (IC50 = 170 μM). Because the total therapeutic concn. of valproic acid ranges from 275 to 700 μM in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chem. approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.
- 160Romani, B.; Kamali Jamil, R.; Hamidi-Fard, M.; Rahimi, P.; Momen, S. B.; Aghasadeghi, M. R.; Allahbakhshi, E. HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatin. Sci. Rep. 2016, 6, 31924, DOI: 10.1038/srep31924[Crossref], [PubMed], [CAS], Google Scholar160https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVSrsb3I&md5=45ca690a1dee464d6002b84708cc5b30HIV-1 Vpr reactivates latent HIV-1 provirus by inducing depletion of class I HDACs on chromatinRomani, Bizhan; Kamali Jamil, Razieh; Hamidi-Fard, Mojtaba; Rahimi, Pooneh; Momen, Seyed Bahman; Aghasadeghi, Mohammad Reza; Allahbakhshi, ElhamScientific Reports (2016), 6 (), 31924CODEN: SRCEC3; ISSN:2045-2322. (Nature Publishing Group)HIV-1 Vpr is an accessory protein that induces proteasomal degrdn. of multiple proteins. We recently showed that Vpr targets class I HDACs on chromatin for proteasomal degrdn. Here we show that Vpr induces degrdn. of HDAC1 and HDAC3 in HIV-1 latently infected J-Lat cells. Degrdn. of HDAC1 and HDAC3 was also obsd. on the HIV-1 LTR and as a result, markers of active transcription were recruited to the viral promoter and induced viral activation. Knockdown of HDAC1 and HDAC3 activated the latent HIV-1 provirus and complementation with HDAC3 inhibited Vpr-induced HIV-1 reactivation. Viral reactivation and degrdn. of HDAC1 and HDAC3 was conserved among Vpr proteins of HV-1 group M. Serum Vpr isolated from patients or the release of virion-incorporated Vpr from viral lysates also activated HIV-1 in latently infected cell lines and PBMCs from HIV-1 infected patients. Our results indicate that Vpr counteracts HIV-1 latency by inducing proteasomal degrdn. of HDAC1 and 3 leading to reactivation of the viral promoter.
- 161Romani, B.; Baygloo, N. S.; Hamidi-Fard, M.; Aghasadeghi, M. R.; Allahbakhshi, E. HIV-1 Vpr protein induces proteasomal degradation of chromatin-associated class I HDACs to overcome latent infection of macrophages. J. Biol. Chem. 2016, 291, 2696– 2711, DOI: 10.1074/jbc.M115.689018[Crossref], [PubMed], [CAS], Google Scholar161https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XitVOqtrk%253D&md5=c2749945626e80cd7d5662b3f3ffd39bHIV-1 Vpr Protein Induces Proteasomal Degradation of Chromatin-associated Class I HDACs to Overcome Latent Infection of MacrophagesRomani, Bizhan; Baygloo, Nima Shaykh; Hamidi-Fard, Mojtaba; Aghasadeghi, Mohammad Reza; Allahbakhshi, ElhamJournal of Biological Chemistry (2016), 291 (6), 2696-2711CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Mechanisms underlying HIV-1 latency remain among the most crucial questions that need to be answered to adopt strategies for purging the latent viral reservoirs. Here the authors show that HIV-1 accessory protein Vpr induces depletion of class I HDACs, including HDAC1, 2, 3, and 8, to overcome latency in macrophages. The authors found that Vpr binds and depletes chromatin-assocd. class I HDACs through a VprBP-dependent mechanism, with HDAC3 as the most affected class I HDAC. De novo expression of Vpr in infected macrophages induced depletion of HDAC1 and 3 on the HIV-1 LTR that was assocd. with hyperacetylation of histones on the HIV-1 LTR. As a result of hyperacetylation of histones on HIV-1 promotor, the virus established an active promotor and this contributed to the acute infection of macrophages. Collectively, HIV-1 Vpr down-regulates class I HDACs on chromatin to counteract latent infections of macrophages.
- 162Bhaskara, S.; Chyla, B. J.; Amann, J. M.; Knutson, S. K.; Cortez, D.; Sun, Z. W.; Hiebert, S. W. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol. Cell 2008, 30, 61– 72, DOI: 10.1016/j.molcel.2008.02.030[Crossref], [PubMed], [CAS], Google Scholar162https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXkvFegurY%253D&md5=6b54eb096e03b39fa255c0ce5a213035Deletion of Histone deacetylase 3 reveals critical roles in S phase progression and DNA damage controlBhaskara, Srividya; Chyla, Brenda J.; Amann, Joseph M.; Knutson, Sarah K.; Cortez, David; Sun, Zu-Wen; Hiebert, Scott W.Molecular Cell (2008), 30 (1), 61-72CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)Histone deacetylases (HDACs) are enzymes that modify key residues in histones to regulate chromatin architecture, and they play a vital role in cell survival, cell-cycle progression, and tumorigenesis. To understand the function of Hdac3, a crit. component of the N-CoR/SMRT repression complex, a conditional allele of Hdac3 was engineered. Cre-recombinase-mediated inactivation of Hdac3 led to a delay in cell-cycle progression, cell-cycle-dependent DNA damage, and apoptosis in mouse embryonic fibroblasts (MEFs). While no overt defects in mitosis were obsd. in Hdac3-/- MEFs, including normal H3Ser10 phosphorylation, DNA damage was obsd. in Hdac3-/- interphase cells, which appears to be assocd. with defective DNA double-strand break repair. Moreover, we noted that Hdac3-/- MEFs were protected from DNA damage when quiescent, which may provide a mechanistic basis for the action of HDAC inhibitors on cycling tumor cells.
- 163Nishimoto, K.; Niida, H.; Uchida, C.; Ohhata, T.; Kitagawa, K.; Motegi, A.; Suda, T.; Kitagawa, M. HDAC3 is required for XPC recruitment and nucleotide excision repair of DNA damage induced by UV irradiation. Mol. Cancer Res. 2020, 18, 1367– 1378, DOI: 10.1158/1541-7786.MCR-20-0214[Crossref], [PubMed], [CAS], Google Scholar163https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXit1SitLfM&md5=e4191c0c8f2d2b23ba564496ae2f02cbHDAC3 is required for XPC recruitment and nucleotide excision repair of DNA damage induced by UV irradiationNishimoto, Koji; Niida, Hiroyuki; Uchida, Chiharu; Ohhata, Tatsuya; Kitagawa, Kyoko; Motegi, Akira; Suda, Takafumi; Kitagawa, MasatoshiMolecular Cancer Research (2020), 18 (9), 1367-1378CODEN: MCROC5; ISSN:1541-7786. (American Association for Cancer Research)Recent studies have demonstrated that lysine acetylation of histones is crucial for nucleotide excision repair (NER) by relaxing the chromatin structure, which facilitates the recruitment of repair factors. However, few studies have focused on the contribution of histone deacetylases (HDAC) to NER. Here, we found that histone H3 Lys14 (H3K14) was deacetylated by HDAC3 after UV irradn. Depletion of HDAC3 caused defects in cyclobutene pyrimidine dimer excision and sensitized cells to UV irradn. HDAC3-depleted cells had impaired unscheduled DNA synthesis, but not recovery of RNA synthesis, which indicates that HDAC3 was required for global genome NER. Moreover, xeroderma pigmentosum, complementation group C (XPC) accumulation at the local UV-irradiated area was attenuated in HDAC3-depleted cells. In addn. to the delay of XPC accumulation at DNA damage sites, XPC ubiquitylation was inhibited in HDAC3-depleted cells. These results suggest that the deacetylation of histone H3K14 by HDAC3 after UV irradn. contributes to XPC recruitment to DNA lesions to promote global genome NER. Implications: Involvement of histone deacetylation for XPC accumulation after UV irradn. indicates conversion of chromatin structure is essential for nucleotide excision repair in human cancer cells.
- 164Long, J.; Fang, W. Y.; Chang, L.; Gao, W. H.; Shen, Y.; Jia, M. Y.; Zhang, Y. X.; Wang, Y.; Dou, H. B.; Zhang, W. J.; Zhu, J.; Liang, A. B.; Li, J. M.; Hu, J. Targeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage response. Leukemia 2017, 31, 2761– 2770, DOI: 10.1038/leu.2017.130[Crossref], [PubMed], [CAS], Google Scholar164https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXotVyiu74%253D&md5=bb06860d8d48faa24985aa0257d9da1fTargeting HDAC3, a new partner protein of AKT in the reversal of chemoresistance in acute myeloid leukemia via DNA damage responseLong, J.; Fang, W. Y.; Chang, L.; Gao, W. H.; Shen, Y.; Jia, M. Y.; Zhang, Y. X.; Wang, Y.; Dou, H. B.; Zhang, W. J.; Zhu, J.; Liang, A. B.; Li, J. M.; Hu, JiongLeukemia (2017), 31 (12), 2761-2770CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Resistance to cytotoxic chemotherapy drugs remains as the major cause of treatment failure in acute myeloid leukemia. Histone deacetylases (HDAC) are important regulators to maintain chromatin structure and control DNA damage; nevertheless, how each HDAC regulates genome stability remains unclear, esp. under genome stress conditions. Here, we identified a mechanism by which HDAC3 regulates DNA damage repair and mediates resistance to chemotherapy drugs. In addn. to inducing DNA damage, chemotherapy drugs trigger upregulation of HDAC3 expression in leukemia cells. Using genetic and pharmacol. approaches, we show that HDAC3 contributes to chemotherapy resistance by regulating the activation of AKT, a well-documented factor in drug resistance development. HDAC3 binds to AKT and deacetylates it at the site Lys20, thereby promoting the phosphorylation of AKT. Chemotherapy drug exposure enhances the interaction between HDAC3 and AKT, resulting in decrease in AKT acetylation and increase in AKT phosphorylation. Whereas HDAC3 depletion or inhibition abrogates these responses and meanwhile sensitizes leukemia cells to chemotoxicity-induced apoptosis. Importantly, in vivo HDAC3 suppression reduces leukemia progression and sensitizes MLL-AF9+ leukemia to chemotherapy. Our findings suggest that combination therapy with HDAC3 inhibitor and genotoxic agents may constitute a successful strategy for overcoming chemotherapy resistance.
- 165Li, X.; Inks, E. S.; Li, X.; Hou, J.; Chou, C. J.; Zhang, J.; Jiang, Y.; Zhang, Y.; Xu, W. Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity. J. Med. Chem. 2014, 57, 3324– 3341, DOI: 10.1021/jm401877m[ACS Full Text], [CAS], Google Scholar165https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsFOjsr4%253D&md5=4e86a4e7c9fda199bdd3cb12730db1daDiscovery of the First N-Hydroxycinnamamide-Based Histone Deacetylase 1/3 Dual Inhibitors with Potent Oral Antitumor ActivityLi, Xiaoyang; Inks, Elizabeth S.; Li, Xiaoguang; Hou, Jinning; Chou, C. James; Zhang, Jian; Jiang, Yuqi; Zhang, Yingjie; Xu, WenfangJournal of Medicinal Chemistry (2014), 57 (8), 3324-3341CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based histone deacetylase inhibitors (HDACIs), among which the representative compd. I exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using I as lead, among which, compd. II gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Several of these compds. showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compd. II as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.
- 166Spurling, C. C.; Godman, C. A.; Noonan, E. J.; Rasmussen, T. P.; Rosenberg, D. W.; Giardina, C. HDAC3 overexpression and colon cancer cell proliferation and differentiation. Mol. Carcinog. 2008, 47, 137– 147, DOI: 10.1002/mc.20373[Crossref], [PubMed], [CAS], Google Scholar166https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXit1Sgtrc%253D&md5=2c4b1c714668ffe205c71fda2cff368fHDAC3 overexpression and colon cancer cell proliferation and differentiationSpurling, Colleen C.; Godman, Cassandra A.; Noonan, Emily J.; Rasmussen, Theodore P.; Rosenberg, Daniel W.; Giardina, CharlesMolecular Carcinogenesis (2008), 47 (2), 137-147CODEN: MOCAE8; ISSN:0899-1987. (Wiley-Liss, Inc.)An immunohistochem. anal. of human colorectal adenocarcinomas showed that cancer cells express widely varying levels of HDAC3. The SW480 colon cancer cell line was found to express high levels of HDAC3 compared to other colon cancer cell lines. P21 was poorly induced in SW480 cells relative to the lower HDAC3-expressing HT-29 cells. RNAi-induced redn. of HDAC3 in SW480 cells increased their constitutive, butyrate-, TSA-, and TNF-α-induced expression of p21, but did not cause all the gene expression changes induced upon general histone deacetylase (HDAC) inhibition. SW480 cells with lower HDAC3 expression appeared to be poised for gene expression responses with increased histone H4-K12 acetylation, but not K5, K8, or K16 acetylation. Even though p21 was readily activated in HT29 cells, HDAC3 siRNA nonetheless stimulated p21 expression in these cells to a greater degree than HDAC1 and HDAC2 siRNA. SW480 cells with lower HDAC3 levels displayed an enhanced cell cycle arrest and growth inhibition by butyrate, but without changes in apoptosis or sensitivity to chemotherapeutic agents. As reported for other colon cancer cell lines, butyrate induced the rapid downregulation of the secretory cell differentiation markers mucin 2 and intestinal trefoil factor in SW480 cells. Interestingly, selective HDAC3 inhibition was sufficient to downregulate these genes. Our data support a central role for HDAC3 in regulating the cell proliferation and differentiation of colon cancer cells and suggest a potential mechanism by which colon cancers may become resistant to luminal butyrate.
- 167Mariadason, J. M. Dissecting HDAC3-mediated tumor progression. Cancer Biol. Ther. 2008, 7, 1581– 1583, DOI: 10.4161/cbt.7.10.6863[Crossref], [PubMed], [CAS], Google Scholar167https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktL3M&md5=71131081bb89241d463248a28db442bbDissecting HDAC3-mediated tumor progressionMariadason, John M.Cancer Biology & Therapy (2008), 7 (10), 1581-1583CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)A review. The research of Godman et al. (2008) entitled, \"HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling\" is reviewed with commentary and refs. The authors provided new insight into mechanisms by which histone deacetylase (HDAC)3 facilitates growth and survival of colon cancer cells in vitro. They showed that approx. 50% of the sequences are similarly altered in response to 18-h histone deacetylase inhibitors (HDACi) treatment. They further showed that the silencing of HDAC3 results in increased expression of several components of the TGFβ and interferon signaling pathways and in the modulation of components of the Wnt signaling pathway. Addnl., their data revealed that both transient and stable knockdown of HDAC3 induces expression of VDR mRNA and protein, and importantly, confers sensitivity of SW480 cells to vitamin D-induced growth inhibition.
- 168Godman, C. A.; Joshi, R.; Tierney, B. R.; Greenspan, E.; Rasmussen, T. P.; Wang, H. W.; Shin, D. G.; Rosenberg, D. W.; Giardina, C. HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signaling. Cancer Biol. Ther. 2008, 7, 1570– 1580, DOI: 10.4161/cbt.7.10.6561[Crossref], [PubMed], [CAS], Google Scholar168https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsFWktLzF&md5=7c87537af734a508cb5f4714bf467fd4HDAC3 impacts multiple oncogenic pathways in colon cancer cells with effects on Wnt and vitamin D signalingGodman, Cassandra A.; Joshi, Rashmi; Tierney, Brendan R.; Greenspan, Emily; Rasmussen, Theodore P.; Wang, Hsin-wei; Shin, Dong-Guk; Rosenberg, Daniel W.; Giardina, CharlesCancer Biology & Therapy (2008), 7 (10), 1570-1580CODEN: CBTAAO; ISSN:1538-4047. (Landes Bioscience)Histone deacetylase 3 (HDAC3) is overexpressed in approx. half of all colon adenocarcinomas. We took an RNAi approach to det. how HDAC3 influenced chromatin modifications and the expression of growth regulatory genes in colon cancer cells. A survey of histone modifications revealed that HDAC3 knockdown in SW480 cells significantly increased histone H4-K12 acetylation, a modification present during chromatin assembly that has been implicated in imprinting. This modification was found to be most prominent in proliferating cells in the intestinal crypt and in APCMin tumors, but was less pronounced in the tumors that overexpress HDAC3. Gene expression profiling of SW480 revealed that HDAC3 shRNA impacted the expression of genes in the Wnt and vitamin D signaling pathways. The impact of HDAC3 on Wnt signaling was complex, with both pos. and neg. effects obsd. However, long-term knockdown of HDAC3 suppressed β-catenin translocation from the plasma membrane to the nucleus, and increased expression of Wnt inhibitors TLE1, TLE4 and SMO. HDAC3 knockdown also enhanced expression of the TLE1 and TLE4 repressors in HT-29 and HCT116 cells. HDAC3 shRNA enhanced expression of the vitamin D receptor in SW480 and HCT116 cells, and rendered SW480 cells sensitive to 1,25-dihydroxyvitamin D3. We propose that HDAC3 overexpression alters the epigenetic programming of colon cancer cells to impact intracellular Wnt signaling and their sensitivity to external growth regulation by vitamin D.
- 169Liu, K. H.; Fu, J.; Zhou, N.; Yin, W.; Yang, Y. Y.; Ouyang, S. X.; Liang, Y. M. 1,25-Dihydroxyvitamin D3 prevents epithelial-mesenchymal transition of HMrSV5 human peritoneal mesothelial cells by inhibiting histone deacetylase 3 (HDAC3) and increasing vitamin D receptor (VDR) expression through the Wnt/β-Catenin signaling pathway. Med. Sci. Monit. 2019, 25, 5892– 5902, DOI: 10.12659/MSM.916313[Crossref], [PubMed], [CAS], Google Scholar169https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXks1ylsL0%253D&md5=f34d51bd4a5dec86dcb55651da029dda1,25-dihydroxyvitamin D3 prevents epithelialmesenchymal transition of HMrSV5 human peritoneal mesothelial cells by inhibiting histone deacetylase 3 (HDAC3) and increasing vitamin D receptor (VDR) expression through the Wnt/β-catenin signaling pathwayLiu, Kang-Han; Fu, Jia; Zhou, Nan; Yin, Wei; Yang, Yi-Ya; Ouyang, Sha-Xi; Liang, Yu-MeiMedical Science Monitor (2019), 25 (), 5892-5902CODEN: MSMOFR; ISSN:1643-3750. (International Scientific Information, Inc.)Background: Peritoneal dialysis is the most common treatment for end-stage renal disease. However, peritoneal fibrosis resulting from long-term peritoneal dialysis restricts peritoneal ultrafiltration. Previous studies have shown a role for 1,25-dihydroxyvitamin D3 (1,25[OH]2 D3) in preventing fibrosis, but the potential mechanisms remain unknown. This study aimed to investigate the role of 1,25(OH)2 D3 in epithelial-mesenchymal transition (EMT) and the downstream signaling pathway in HMrSV5 human peritoneal mesothelial cells in vitro. Material/Methods: An in vitro cell model of peritoneal fibrosis was established using the HMrSV5 human peritoneal mesothelial cell line. High glucose and lipopolysaccharide (LPS) culture conditions, with or without 1,25(OH)2 D3, were used. Wnt agonist 1, a Wnt signaling pathway activator, was applied. Quant. real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the vitamin D receptor (VDR) and histone deacetylase 3 (HDAC3) gene and protein expression levels, β -catenin, and EMT-assocd. biomarkers. Results: High glucose plus LPS culture medium inhibited cell proliferation, induced cell apoptosis and promoted EMT in HMrSV5 cells, which was reversed by 1,25(OH)2 D3 by down-regulation of HDAC3 and upregulation of VDR. HDAC3 inhibited VDR gene expression. The expression of EMT-assocd. biomarkers was increased by Wnt agonist 1 and inhibited by 1,25(OH)2 D3. Conclusions: In HMrSV5 human peritoneal mesothelial cells, 1,25(OH)2 D3 reversed EMT by inhibiting the expression of HDAC3 and upregulating VDR gene expression via the Wnt/β-catenin signaling pathway.
- 170Bacon, T.; Seiler, C.; Wolny, M.; Hughes, R.; Watson, P.; Schwabe, J.; Grigg, R.; Peckham, M. Histone deacetylase 3 indirectly modulates tubulin acetylation. Biochem. J. 2015, 472, 367– 377, DOI: 10.1042/BJ20150660[Crossref], [PubMed], [CAS], Google Scholar170https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFGnsrnO&md5=1362a80cfda02865bda00b9f79b96a80Histone deacetylase 3 indirectly modulates tubulin acetylationBacon, Travis; Seiler, Caroline; Wolny, Marcin; Hughes, Ruth; Watson, Peter; Schwabe, John; Grigg, Ronald; Peckham, MichelleBiochemical Journal (2015), 472 (3), 367-377CODEN: BIJOAK; ISSN:0264-6021. (Portland Press Ltd.)Histone deacetylase 3 (HDAC3), a member of the Class I subfamily of HDACs, is found in both the nucleus and the cytoplasm. Its roles in the nucleus have been well characterized, but its cytoplasmic roles are still not elucidated fully. Blocking HDAC3 activity using MI192, a compd. specific for HDAC3, modulated tubulin acetylation in the human prostate cancer cell line PC3. A brief 1 h treatment of PC3 cells with MI192 significantly increased levels of tubulin acetylation and ablated the dynamic behavior of microtubules in live cells. The siRNA-mediated knockdown (KD) of HDAC3 in PC3 cells, significantly increased levels of tubulin acetylation, and overexpression reduced it. However, the active HDAC3-silencing mediator of retinoic and thyroid receptors (SMRT)-deacetylase-activating domain (DAD) complex did not directly deacetylate tubulin in vitro. These data suggest that HDAC3 indirectly modulates tubulin acetylation.
- 171Villagra, A.; Sotomayor, E. M.; Seto, E. Histone deacetylases and the immunological network: implications in cancer and inflammation. Oncogene 2010, 29, 157– 173, DOI: 10.1038/onc.2009.334[Crossref], [PubMed], [CAS], Google Scholar171https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtlSqsLbI&md5=73bed9eb86b3d8c35e02ce73e99753b3Histone deacetylases and the immunological network: implications in cancer and inflammationVillagra, A.; Sotomayor, E. M.; Seto, E.Oncogene (2010), 29 (2), 157-173CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)A review. The initiation, magnitude and duration of an immune response against antigens are a tightly regulated process involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is crit. for allowing efficient immune response against foreign antigens while preventing autoimmune attack against self-antigens. In recent years, much effort has been devoted to understanding immune evasion by cancer cells. Also, significant advances have been made in mechanistically understanding the role of pro- and anti-inflammatory cytokines in the regulation of immune responses against antigens, including those expressed by tumors. However, the authors still know very little about the regulation of inflammatory/anti-inflammatory genes in their natural setting, the chromatin substrate. Several mechanisms have been identified to influence chromatin flexibility and allow dynamic changes in gene expression. Among those, chromatin modifications induced by acetylation and deacetylation of histone tails have gained wide attention. In this study, the authors discuss the role of histone deacetylases in the transcriptional regulation of genes involved in the inflammatory response and how these enzymes coordinate the dynamic expression of these genes during an immune response. This emerging knowledge is opening new avenues to better understand epigenetic regulation of inflammatory responses and providing new mol. targets for either amplifying or ameliorating immune responses.
- 172Zhang, Y.; Tuzova, M.; Xiao, Z. X.; Cruikshank, W. W.; Center, D. M. Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP. J. Immunol. 2008, 180, 402– 408, DOI: 10.4049/jimmunol.180.1.402[Crossref], [PubMed], [CAS], Google Scholar172https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD2sjlvVChsA%253D%253D&md5=c94adad4f3ad436057bc31fd643388fdPro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABPZhang Yujun; Tuzova Marina; Xiao Zhi-Xiong J; Cruikshank William W; Center David MJournal of immunology (Baltimore, Md. : 1950) (2008), 180 (1), 402-8 ISSN:0022-1767.Pro-IL-16 is a PDZ domain-containing protein expressed in T cells. Our previous work showed that upon activation of normal T cells, pro-IL-16 mRNA and protein are diminished in close correlation to the down-regulation of p27KIP1 protein. In addition, we showed that pro-IL-16 regulates the transcription of Skp2, the mechanism of which, however, remains elusive. In this study, we identified GA binding protein beta1 subunit (GABPbeta1) and histone deacetylase 3 (HDAC3) as binding partners of pro-IL-16. Interestingly, both GABPbeta1 and HDAC3 have canonical PDZ-binding motifs and specifically bind to the first and second PDZ domain of pro-IL-16, respectively. Heat shock cognate protein 70 (HSC70) also copurified with the GST-PDZ1-containing fragment but lacks a C-terminal PDZ binding motif, suggesting that it binds through a different mechanism. We further showed that pro-IL-16 is located in a GABP transcriptional complex bound to the Skp2 promoter. In addition, we demonstrated that HDAC activity is critical for pro-IL-16-induced cell cycle arrest. Taken altogether, these data suggest that pro-IL-16 forms a complex with GABPbeta1 and HDAC3 in suppressing the transcription of Skp2. Thus, this study has revealed a novel mechanism with which pro-IL-16 regulates T cell growth through the Skp2-p27KIP1 pathway.
- 173Ozawa, Y.; Towatari, M.; Tsuzuki, S.; Hayakawa, F.; Maeda, T.; Miyata, Y.; Tanimoto, M.; Saito, H. Histone deacetylase 3 associates with and represses the transcription factor GATA-2. Blood 2001, 98, 2116– 2123, DOI: 10.1182/blood.V98.7.2116[Crossref], [PubMed], [CAS], Google Scholar173https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD3MXnsVChtr4%253D&md5=243533275b3caf737f571c73081070a2Histone deacetylase 3 associates with and represses the transcription factor GATA-2Ozawa, Yukiyasu; Towatari, Masayuki; Tsuzuki, Shinobu; Hayakawa, Fumihiko; Maeda, Takahiro; Miyata, Yasuhiko; Tanimoto, Mitsune; Saito, HidehikoBlood (2001), 98 (7), 2116-2123CODEN: BLOOAW; ISSN:0006-4971. (American Society of Hematology)The zinc finger transcription factor GATA-2 plays a crit. role in the survival and proliferation of hematopoietic stem cells. This study examd. the interaction of GATA-2 with histone deacetylases (HDACs) to define the involvement of HDACs in the regulation of GATA-2 function. GATA-2 directly assocs. with HDAC3 but not with HDAC1. Consistent with this, HDAC3 suppressed the transcriptional potential of GATA-2, whereas HDAC1 did not affect GATA-2-dependent transcription. Results further demonstrated that GATA-2 and HDAC3 colocalized in the nucleus. These results identify GATA-2 as a nuclear target for HDAC3-mediated repression. Furthermore, GATA-2 also directly assocd. with HDAC5 but not with other class II HDACs examd., i.e., HDAC4 and HDAC6. This is the first demonstration that a tissue-specific transcription factor directly and selectively interacts with HDAC3 and HDAC5 among HDAC family members.
- 174Kumar, M. S.; Hancock, D. C.; Molina-Arcas, M.; Steckel, M.; East, P.; Diefenbacher, M.; Armenteros-Monterroso, E.; Lassailly, F.; Matthews, N.; Nye, E.; Stamp, G.; Behrens, A.; Downward, J. GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 2012, 149, 642– 655, DOI: 10.1016/j.cell.2012.02.059[Crossref], [PubMed], [CAS], Google Scholar174https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xmt1Kjs7c%253D&md5=da14f8854da4b616c3d6e161364fabb9The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancerKumar, Madhu S.; Hancock, David C.; Molina-Arcas, Miriam; Steckel, Michael; East, Phillip; Diefenbacher, Markus; Armenteros-Monterroso, Elena; Lassailly, Francois; Matthews, Nik; Nye, Emma; Stamp, Gordon; Behrens, Axel; Downward, JulianCell (Cambridge, MA, United States) (2012), 149 (3), 642-655CODEN: CELLB5; ISSN:0092-8674. (Cell Press)Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clin. approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation.
- 175Krämer, O. H.; Knauer, S. K.; Greiner, G.; Jandt, E.; Reichardt, S.; Gührs, K. H.; Stauber, R. H.; Böhmer, F. D.; Heinzel, T. A phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev. 2009, 23, 223– 235, DOI: 10.1101/gad.479209[Crossref], [PubMed], [CAS], Google Scholar175https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BD1M%252FpvVOrtg%253D%253D&md5=6dca44d82ad68948ceab4b2957c223bbA phosphorylation-acetylation switch regulates STAT1 signalingKramer Oliver H; Knauer Shirley K; Greiner Georg; Jandt Enrico; Reichardt Sigrid; Guhrs Karl-Heinz; Stauber Roland H; Bohmer Frank D; Heinzel ThorstenGenes & development (2009), 23 (2), 223-35 ISSN:.Cytokines such as interferons (IFNs) activate signal transducers and activators of transcription (STATs) via phosphorylation. Histone deacetylases (HDACs) and the histone acetyltransferase (HAT) CBP dynamically regulate STAT1 acetylation. Here we show that acetylation of STAT1 counteracts IFN-induced STAT1 phosphorylation, nuclear translocation, DNA binding, and target gene expression. Biochemical and genetic experiments altering the HAT/HDAC activity ratio and STAT1 mutants reveal that a phospho-acetyl switch regulates STAT1 signaling via CBP, HDAC3, and the T-cell protein tyrosine phosphatase (TCP45). Strikingly, inhibition of STAT1 signaling via CBP-mediated acetylation is distinct from the functions of this HAT in transcriptional activation. STAT1 acetylation induces binding of TCP45, which catalyzes dephosphorylation and latency of STAT1. Our results provide a deeper understanding of the modulation of STAT1 activity. These findings reveal a new layer of physiologically relevant STAT1 regulation and suggest that a previously unidentified balance between phosphorylation and acetylation affects cytokine signaling.
- 176Hanigan, T. W.; Aboukhatwa, S. M.; Taha, T. Y.; Frasor, J.; Petukhov, P. A. Divergent JNK phosphorylation of HDAC3 in triple-negative breast cancer cells determines HDAC inhibitor binding and selectivity. Cell Chem. Biol. 2017, 24, 1356– 1367, DOI: 10.1016/j.chembiol.2017.08.015[Crossref], [PubMed], [CAS], Google Scholar176https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFGnsrfF&md5=f63d68cc73cf1175890f39b6a91301bcDivergent JNK Phosphorylation of HDAC3 in Triple-Negative Breast Cancer Cells Determines HDAC Inhibitor Binding and SelectivityHanigan, Thomas W.; Aboukhatwa, Shaimaa M.; Taha, Taha Y.; Frasor, Jonna; Petukhov, Pavel A.Cell Chemical Biology (2017), 24 (11), 1356-1367.e8CODEN: CCBEBM; ISSN:2451-9448. (Cell Press)Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACis) is unclear. In this study, we developed a method that identified a 3- to 16-fold increase in HDACi selectivity for HDAC3 in triple-neg. breast cancer (TNBC) cells in comparison with luminal subtypes that was not predicted by current practice measurements with recombinant proteins. We found this increase was caused by c-Jun N-terminal kinase (JNK) phosphorylation of HDAC3, was independent of HDAC3 complex compn. or subcellular localization, and was assocd. with a 5-fold increase in HDAC3 enzymic activity. This study points to HDAC3 and the JNK axes as targets in TNBC, highlights how HDAC phosphorylation affects HDACi binding and selectivity, and outlines a method to identify changes in individual HDAC isoforms catalytic activity, applicable to any disease state.
- 177Oie, S.; Matsuzaki, K.; Yokoyama, W.; Murayama, A.; Yanagisawa, J. HDAC3 regulates stability of estrogen receptor α mRNA. Biochem. Biophys. Res. Commun. 2013, 432, 236– 241, DOI: 10.1016/j.bbrc.2013.02.007[Crossref], [PubMed], [CAS], Google Scholar177https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjtFWhsrk%253D&md5=e5cd396c2f8c4ed919ce69d4dbe3e4c0HDAC3 regulates stability of estrogen receptor α mRNAOie, Shohei; Matsuzaki, Kazuya; Yokoyama, Wataru; Murayama, Akiko; Yanagisawa, JunnBiochemical and Biophysical Research Communications (2013), 432 (2), 236-241CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Estrogen receptor alpha (ERα) expression is a risk factor for breast cancer. HDAC inhibitors have been demonstrated to down-regulate ERα expression in ERα-pos. breast cancer cell lines, but the mol. mechanisms are poorly understood.Here, we showed that HDAC inhibitors decrease the stability of ERα mRNA, and that knockdown of HDAC3 decreases the stability of ERα mRNA and suppresses estrogen-dependent proliferation of ERα-pos. MCF-7 breast cancer cells. In the Oncomine database, expression levels of HDAC3 in ERα-pos. tumors are higher than those in ERα-neg. tumors, thus suggesting that HDAC3 is necessary for ERα mRNA stability, and is involved in the estrogen-dependent proliferation of ERα-pos. tumors.
- 178Cui, Z.; Xie, M.; Wu, Z.; Shi, Y. Relationship between histone deacetylase 3 (HDAC3) and breast cancer. Med. Sci. Monit. 2018, 24, 2456– 2464, DOI: 10.12659/MSM.906576[Crossref], [PubMed], [CAS], Google Scholar178https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVGjtLfJ&md5=ee400af1bc4c2e2dbce592fed4b6b9dfRelationship between histone deacetylase 3 (HDAC3) and breast cancerCui, Zhuhong; Xie, Mingjun; Wu, Zhenru; Shi, YujunMedical Science Monitor (2018), 24 (), 2456-2464CODEN: MSMOFR; ISSN:1643-3750. (International Scientific Information, Inc.)Background: The modification of histone acetylation and deacetylation is the most important mechanism of chromatin re- modeling. These modifications are a subset of epigenetic alterations which affect tumorigenesis and progression through changes in gene expression and cell growth. Results of histone modification studies prompted us to explore the therapeutic and prognostic significance of histone deacetylase 3 (HDAC3) expression in patients with breast cancer. Material/Methods: Immunohistochem. (IHC) staining was used to detect HDAC3 expression in a tissue microarray (TMA) that included 145 patients diagnosed with invasive ductal breast carcinoma. IHC scoring was used to evaluate the staining intensity and the proportion of pos. cells. Results: HDAC3 expression was significantly correlated with estrogen receptor (ER)-neg. expression P=0.036) and progesterone receptor (PR)-neg. expression P=0.024). Addnl., HDAC3 expression was significantly pos. correlated with human epidermal growth factor 2 (HER2) overexpression P=0.037. Our study also indicated that high expression of HDAC3 was more frequently obsd. in breast tumors with PT2 classification (74%) vs. PT1 (50.0%) and PT3 (71.4%) P=0.040. Furthermore, HDAC3 was correlated with clin. stage II P=0.046. Univariate and multivariate survival analyses showed that high expression of HDAC3 was correlated with poor overall survival (OS) P=0.029 and P=0.033, resp. in patients without lymph node involvement. Conclusions: High HDAC3 expression is closely correlated with ER-neg. expression, PR-neg. expression, HER2 over-expression, PT stage, and clin. stage of breast tumors. HDAC3 may be an appropriate prognostic indicator in patients with invasive ductal breast cancer.
- 179Kim, H. C.; Choi, K. C.; Choi, H. K.; Kang, H. B.; Kim, M. J.; Lee, Y. H.; Lee, O. H.; Lee, J.; Kim, Y. J.; Jun, W.; Jeong, J. W.; Yoon, H. G. HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cells. Cell. Mol. Life Sci. 2010, 67, 3499– 3510, DOI: 10.1007/s00018-010-0388-5[Crossref], [PubMed], [CAS], Google Scholar179https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhtFOrtb%252FJ&md5=98c63a68c8474d1c9cc622ae6faa85e0HDAC3 selectively represses CREB3-mediated transcription and migration of metastatic breast cancer cellsKim, Han-Cheon; Choi, Kyung-Chul; Choi, Hyo-Kyoung; Kang, Hee-Bum; Kim, Mi-Jeong; Lee, Yoo-Hyun; Lee, Ok-Hee; Lee, Jeongmin; Kim, Young Jun; Jun, Woojin; Jeong, Jae-Wook; Yoon, Ho-GeunCellular and Molecular Life Sciences (2010), 67 (20), 3499-3510CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Verlag)We identified CREB3 as a novel HDAC3-interacting protein in a yeast two-hybrid screen for HDAC3-interacting proteins. Among all class I HDACs, CREB3 specifically interacts with HDAC3, in vitro and in vivo. HDAC3 efficiently inhibited CREB3-enhanced NF-κB activation, whereas the other class I HDACs did not alter NF-κB-dependent promoter activities or the expression of NF-κB target genes. Importantly, both knock-down of CREB3 and overexpression of HDAC3 suppressed the transcriptional activation of the novel CREB3-regulated gene, CXCR4. Furthermore, CREB3 was shown to bind to the CRE element in the CXCR4 promoter and to activate the transcription of the CXCR4 gene by causing dissocn. of HDAC3 and subsequently increasing histone acetylation. Importantly, both the depletion of HDAC3 and the overexpression of CREB3 substantially increased the migration of MDA-MB-231 metastatic breast cancer cells. Taken together, these findings suggest that HDAC3 selectively represses CREB3-mediated transcriptional activation and chemotactic signalling in human metastatic breast cancer cells.
- 180Hu, G.; He, N.; Cai, C.; Cai, F.; Fan, P.; Zheng, Z.; Jin, X. HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancer. Pancreatology 2019, 19, 383– 389, DOI: 10.1016/j.pan.2019.01.011[Crossref], [PubMed], [CAS], Google Scholar180https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhsVegs7g%253D&md5=31dc9dae3f2175097134f6d08c7b57b9HDAC3 modulates cancer immunity via increasing PD-L1 expression in pancreatic cancerHu, Guofu; He, Nan; Cai, Chuanqi; Cai, Fei; Fan, Ping; Zheng, Zhikun; Jin, XinPancreatology (2019), 19 (2), 383-389CODEN: PANCC2; ISSN:1424-3903. (Elsevier B.V.)Pancreatic ductal adenocarcinoma (PDAC) is the second leading cause of cancer-related deaths worldwide. Despite immune checkpoints based immunotherapy highlights a new therapeutic strategy and achieves a remarkable therapeutic effect in various types of malignant tumors. Pancreatic cancer is one of the non-immunogenic cancers and is resistant to immunotherapy. Programmed death ligand 1 (PD-L1) is expressed on the surface of tumor cells and its level is a key determinant of the checkpoint immunotherapy efficacy. Here, we reported that the specific inhibitor of histone deacetylase 3 (HDAC3) decreased the protein and mRNA level of PD-L1 in pancreatic cancer cells. Furthermore, we showed that HDAC3 was crit. for PD-L1 regulation and pos. correlated with PD-L1 in PDAC patient specimens. Finally, we demonstrated that HDAC3/signal transducer and activator of transcription 3 (STAT3) pathway transcriptionally regulated PD-L1 expression. Collectively, our data contributes to a better understanding of the function of HDAC3 in cancer immunity and the regulatory mechanism of PD-L1. More importantly, these data suggest that the HDAC3 inhibitors might be used to improve immunotherapy in pancreatic cancer.
- 181Liu, X.; Wang, J. H.; Li, S.; Li, L. L.; Huang, M.; Zhang, Y. H.; Liu, Y.; Yang, Y. T.; Ding, R.; Ke, Y. Q. Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase/ERK-MMP-laminin5γ2 signaling pathway. Cancer Sci. 2015, 106, 857– 866, DOI: 10.1111/cas.12684[Crossref], [PubMed], [CAS], Google Scholar181https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVWqtrnE&md5=298f49a02006fde84f98f6b797018c13Histone deacetylase 3 expression correlates with vasculogenic mimicry through the phosphoinositide3-kinase / ERK-MMP-laminin5γ2 signaling pathwayLiu, Xiao; Wang, Ji-Hui; Li, Shun; Li, Lin-Lin; Huang, Min; Zhang, Yong-Hong; Liu, Yang; Yang, Yuan-Tao; Ding, Rui; Ke, Yi-QuanCancer Science (2015), 106 (7), 857-866CODEN: CSACCM; ISSN:1349-7006. (Wiley-Blackwell)Vasculogenic mimicry (VM) refers to the process by which highly aggressive tumor cells mimic endothelial cells to form vessel-like structures that aid in supplying enough nutrients to rapidly growing tumors. Histone deacetylases (HDACs) regulate the expression and activity of numerous mols. involved in cancer initiation and progression. Notably, HDAC3 is overexpressed in the majority of carcinomas. However, thus far, no data are available to support the role of HDAC3 in VM. In this study, we subjected glioma specimens to immunohistochem. and histochem. double-staining methods and found that VM and HDAC3 expression were related to the pathol. grade of gliomas. The presence of VM correlated with HDAC3 expression in glioma tissues. The formation of tubular structures, as detd. by the tube formation assay to evaluate VM, was impaired in U87MG cells when transfected by siRNA or treated with an HDAC3 inhibitor. Importantly, the expression of VM-related mols. such as MMP-2/14 and laminin5γ2 was also affected when HDAC3 expression was altered. Furthermore, U87MG cells were treated with a phosphoinositide 3-kinase (PI3K) inhibitor or/and ERK inhibitor and found that the PI3K and ERK signaling pathways play key roles in VM; whereas, in VM, the two signaling pathways did not act upstream or downstream from each other. Taken together, our findings showed that HDAC3 contributed to VM in gliomas, possibly through the PI3K/ERK-MMPs-laminin5γ2 signaling pathway, which could potentially be a novel therapeutic target for gliomas.
- 182Zhang, B.; Liu, B.; Chen, D.; Setroikromo, R.; Haisma, H. J.; Quax, W. J. Histone deacetylase inhibitors sensitize TRAIL-induced apoptosis in colon cancer cells. Cancers 2019, 11, 645, DOI: 10.3390/cancers11050645[Crossref], [CAS], Google Scholar182https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitV2mt7s%253D&md5=cf3fcfbc36d7d22cc7d49f27c46cd8ebHistone deacetylase inhibitors sensitize TRAIL-induced apoptosis in colon cancer cellsZhang, Baojie; Liu, Bin; Chen, Deng; Setroikromo, Rita; Haisma, Hidde J.; Quax, Wim J.Cancers (2019), 11 (5), 645CODEN: CANCCT; ISSN:2072-6694. (MDPI AG)Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi's), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi's, however, show considerable toxicity constraining clin. use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi's. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi's on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We obsd. that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.
- 183McLeod, A. B.; Stice, J. P.; Wardell, S. E.; Alley, H. M.; Chang, C. Y.; McDonnell, D. P. Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancer. Prostate 2018, 78, 266– 277, DOI: 10.1002/pros.23467[Crossref], [PubMed], [CAS], Google Scholar183https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhslSjsrs%253D&md5=c188c27b16014c50d9e42783141a66a0Validation of histone deacetylase 3 as a therapeutic target in castration-resistant prostate cancerMcLeod, Abigail B.; Stice, James P.; Wardell, Suzanne E.; Alley, Holly M.; Chang, Ching-yi; McDonnell, Donald P.Prostate (Hoboken, NJ, United States) (2018), 78 (4), 266-277CODEN: PRSTDS; ISSN:0270-4137. (Wiley-Blackwell)Background : Whereas the androgen receptor (AR) signaling axis remains a therapeutic target in castration-resistant prostate cancer (CRPC), the emergence of AR mutations and splice variants as mechanisms underlying resistance to contemporary inhibitors of this pathway highlights the need for new therapeutic approaches to target this disease. Of significance in this regard is the considerable preclin. data, indicating that histone deacetylase (HDAC) inhibitors may have utility in the treatment of CRPC. However, the results of clin. studies using HDAC inhibitors (directed against HDAC1, 2, 3, and 8) in CRPC are equivocal, a result that some have attributed to their ability to induce an epithelial to mesenchymal transition (EMT) and neuroendocrine differentiation. We posited that it might be possible to uncouple the beneficial effects of HDAC inhibitors on AR signaling from their undesired activities by targeting specific HDACs as opposed to using the pan-inhibitor strategy that has been employed to date. Methods : The relative abilities of pan- and selective-Class I HDAC inhibitors to attenuate AR-mediated target gene expression and proliferation were assessed in several prostate cancer cell lines. Small interfering RNA (siRNA)-mediated knockdown approaches were used to confirm the importance of of HDAC 1, 2, and 3 expression in these processes. Further, the ability of each HDAC inhibitor to induce the expression of EMT markers (RNA and protein) and EMT-like phenotype(s) (migration) were also assessed. The anti-tumor efficacy of a HDAC3-selective inhibitor, RGFP966, was compared to the pan-HDAC inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in the 22Rv1 xenograft model. Results : Using genetic and pharmacol. approaches we demonstrated that a useful inhibition of AR transcriptional activity, absent the induction of EMT, could be achieved by specifically inhibiting HDAC3. Significantly, we also detd. that HDAC3 inhibitors blocked the activity of the constitutively active AR V7-splice variant and inhibited the growth of xenograft tumors expressing this protein. Conclusions : Our studies provide strong rationale for the near-term development of specific HDAC3 inhibitors for the treatment of CRPC.
- 184Zhang, L.; Chen, Y.; Jiang, Q.; Song, W.; Zhang, L. Therapeutic potential of selective histone deacetylase 3 inhibition. Eur. J. Med. Chem. 2019, 162, 534– 542, DOI: 10.1016/j.ejmech.2018.10.072[Crossref], [PubMed], [CAS], Google Scholar184https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXit12ltLrF&md5=fa992fb99f58bda9baddc1eaaf2d25e4Therapeutic potential of selective histone deacetylase 3 inhibitionZhang, Lihui; Chen, Yiming; Jiang, Qixiao; Song, Weiguo; Zhang, LeiEuropean Journal of Medicinal Chemistry (2019), 162 (), 534-542CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Histone deacetylases (HDACs) are closely related to the occurrence and development of a variety of diseases, such as tumor, inflammation, diabetes mellitus, cardiovascular and neurodegenerative diseases. Inhibition of HDACs by developing HDAC inhibitors has achieved significant progress in the treatment of diseases caused by epigenetic abnormalities, and esp. in the cancer therapy. Isoform selective HDAC inhibitors are emphasized to be disease specific and have less off-target effects and better safety performances. HDAC3 has been illustrated to play specific role in the development of several diseases, and the discovery of HDAC3 selective inhibitors has exhibited potential in the targeted disease treatment. Herein, we summarize the current knowledge about the prospects of selective inhibition of HDAC3 for the drug development.
- 185Zhao, N.; Li, S. W.; Wang, R. Z.; Xiao, M. H.; Meng, Y.; Zeng, C. X.; Fang, J. H.; Yang, J. E.; Zhuang, S. M. Expression of microRNA-195 is transactivated by Sp1 but inhibited by histone deacetylase 3 in hepatocellular carcinoma cells. Biochim. Biophys. Acta, Gene Regul. Mech. 2016, 1859, 933– 942, DOI: 10.1016/j.bbagrm.2016.05.006[Crossref], [CAS], Google Scholar185https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XnvFOis7o%253D&md5=3e1ac1bfafee6067140a18ab1948c84eExpression of microRNA-195 is transactivated by Sp1 but inhibited by histone deacetylase 3 in hepatocellular carcinoma cellsZhao, Na; Li, Siwen; Wang, Ruizhi; Xiao, Manhuan; Meng, Yu; Zeng, Chunxian; Fang, Jian-Hong; Yang, Jine; Zhuang, Shi-MeiBiochimica et Biophysica Acta, Gene Regulatory Mechanisms (2016), 1859 (7), 933-942CODEN: BBAGC6; ISSN:1874-9399. (Elsevier B.V.)MiR-195 expression is frequently reduced in various cancers, but its underlying mechanisms remain unknown. To explore whether abnormal transcription contributed to miR-195 downregulation in hepatocellular carcinoma (HCC), we characterized the -2165-bp site upstream of mature miR-195 as transcription start site and the -2.4 to -2.0-kb fragment as the promoter of miR-195 gene. Subsequent investigation showed that deletion of the predicted Sp1 binding site decreased the miR-195 promoter activity; Sp1 silencing significantly reduced the miR-195 promoter activity and the endogenous miR-195 level; Sp1 directly interacted with the miR-195 promoter in vitro and in vivo. These data suggest Sp1 as a transactivator for miR-195 transcription. Interestingly, miR-195 expression was also subjected to epigenetic regulation. Histone deacetylase 3 (HDAC3) could anchor to the miR-195 promoter via interacting with Sp1 and consequently repress the Sp1-mediated miR-195 transactivation by deacetylating histone in HCC cells. Consistently, substantial increase of HDAC3 protein was detected in human HCC tissues and HDAC3 upregulation was significantly correlated with miR-195 downregulation, suggesting that HDAC3 elevation may represent an important cause for miR-195 redn. in HCC. Our findings uncover the mechanisms underlying the transcriptional regulation and expression deregulation of miR-195 in HCC cells and provide new insight into microRNA biogenesis in cancer cells.
- 186Xu, G. R.; Zhu, H. X.; Zhang, M. H.; Xu, J. H. Histone deacetylase 3 is associated with gastric cancer cell growth via the miR-454-mediated targeting of CHD5. Int. J. Mol. Med. 2017, 41, 155– 163, DOI: 10.3892/ijmm.2017.3225
- 187Yin, Y.; Zhang, M.; Dorfman, R. G.; Li, Y.; Zhao, Z.; Pan, Y.; Zhou, Q.; Huang, S.; Zhao, S.; Yao, Y.; Zou, X. Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibition. Cell Death Dis. 2017, 8, e2856 DOI: 10.1038/cddis.2016.457[Crossref], [PubMed], [CAS], Google Scholar187https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCiur3L&md5=8928a846dd4ad5be1c224e2df90d82b0Histone deacetylase 3 overexpression in human cholangiocarcinoma and promotion of cell growth via apoptosis inhibitionYin, Yuyao; Zhang, Mingming; Dorfman, Robert Gregory; Li, Yang; Zhao, Zhenguo; Pan, Yida; Zhou, Qian; Huang, Shan; Zhao, Shimin; Yao, Yuling; Zou, XiaopingCell Death & Disease (2017), 8 (6), e2856CODEN: CDDEA4; ISSN:2041-4889. (Nature Publishing Group)Histone deacetylase 3 (HDAC3) has an oncogenic role in apoptosis and contributes to the proliferation of cancer cells. MI192 is a novel HDAC3-specific inhibitor that displays antitumor activity in many cancer cell lines. However, the role of HDAC3 and the antitumor activity of its inhibitor MI192 are not known in cholangiocarcinoma (CCA). The present study aims to identify the target of MI192 in CCA as well as evaluate its therapeutic efficacy. CCK8 and colony formation assays showed that HDAC3 overexpression promotes proliferation in CCA cell lines. HDAC3 knockdown or treatment with MI192 decreased CCA cell growth and increased caspase-dependent apoptosis, while apoptosis was partially rescued by HDAC3 overexpression. We demonstrated that MI192 can inhibit the deacetylation activity of HDAC3 and its downstream targets in vitro, and MI192 inhibited xenograft tumor growth in vivo. Immunochem. showed that HDAC3 was upregulated in CCA tissues compared with adjacent normal tissues, and this was correlated with reduced patient survival. Taken together, these results demonstrate for the first time that MI192 targets HDAC3 and induces apoptosis in human CCA cells. MI192 therefore shows the potential as a new drug candidate for CCA therapy.
- 188Zhang, M.; Yin, Y.; Dorfman, R. G.; Zou, T.; Pan, Y.; Li, Y.; Wang, Y.; Zhou, Q.; Zhou, L.; Kong, B.; Friess, H.; Zhang, J.; Zhao, S.; Wang, L.; Zou, X. Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosis. Oncotarget 2017, 8, 99402– 99413, DOI: 10.18632/oncotarget.19660[Crossref], [PubMed], [CAS], Google Scholar188https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1MzitVSksA%253D%253D&md5=142f57cbd288ee72476d0a4524640752Down-regulation of HDAC3 inhibits growth of cholangiocarcinoma by inducing apoptosisZhang Mingming; Yin Yuyao; Li Yang; Wang Yuming; Zhou Lixing; Kong Bo; Wang Lei; Zou Xiaoping; Zhang Mingming; Zhao Shimin; Dorfman Robert G; Zou Tianhui; Pan Yida; Zhang Jun; Zhao Shimin; Zhou Qian; Zhao Shimin; Kong Bo; Friess HelmutOncotarget (2017), 8 (59), 99402-99413 ISSN:.Class I histone deacetylases (HDACs) inhibit expression of tumor suppressor genes by removing acetyl groups from histone lysine residues, thereby increasing cancer cell survival and proliferation. We evaluated the expression of class I HDACs in cholangiocarcinoma (CCA). HDAC3 expression was specifically increased in CCA tissues and correlated with reduced patient survival. HDAC3 overexpression inhibited apoptosis and promoted CCA cell proliferation. Conversely, HDAC3 knockdown or pharmacological inhibition decreased CCA cell growth and increased caspase-dependent apoptosis. Inhibition of class I HDACs blocked HDAC3-catalyzed deacetylation and increased expression of downstream pro-apoptotic targets in vitro and in vivo. These results demonstrate for the first time that down-regulation of HDAC3 induces apoptosis in human CCA cells, indicating that inhibiting HDAC3 may be an effective therapeutic strategy for treating CCA .
- 189Wells, C. E.; Bhaskara, S.; Stengel, K. R.; Zhao, Y.; Sirbu, B.; Chagot, B.; Cortez, D.; Khabele, D.; Chazin, W. J.; Cooper, A.; Jacques, V.; Rusche, J.; Eischen, C. M.; McGirt, L. Y.; Hiebert, S. W. Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One 2013, 8, e68915 DOI: 10.1371/journal.pone.0068915[Crossref], [PubMed], [CAS], Google Scholar189https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1aisrrK&md5=5bbf6c64dd030d2a370d198589079903Inhibition of Histone deacetylase 3 causes replication stress in cutaneous T cell lymphomaWells, Christina E.; Bhaskara, Srividya; Stengel, Kristy R.; Zhao, Yue; Sirbu, Bianca; Chagot, Benjamin; Cortez, David; Khabele, Dineo; Chazin, Walter J.; Cooper, Andrew; Jacques, Vincent; Rusche, James; Eischen, Christine M.; McGirt, Laura Y.; Hiebert, Scott W.PLoS One (2013), 8 (7), e68915CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Given the fundamental roles of histone deacetylases (HDACs) in the regulation of DNA repair, replication, transcription and chromatin structure, it is fitting that therapies targeting HDAC activities are now being explored as anti-cancer agents. In fact, two histone deacetylase inhibitors (HDIs), SAHA and Depsipeptide, are FDA approved for single-agent treatment of refractory cutaneous T cell lymphoma (CTCL). An important target of these HDIs, histone deacetylase 3 (HDAC3), regulates processes such as DNA repair, metab., and tumorigenesis through the regulation of chromatin structure and gene expression. Here we show that HDAC3 inhibition using a first in class selective inhibitor, RGFP966, resulted in decreased cell growth in CTCL cell lines due to increased apoptosis that was assocd. with DNA damage and impaired S phase progression. Through isolation of proteins on nascent DNA (iPOND), we found that HDAC3 was assocd. with chromatin and is present at and around DNA replication forks. DNA fiber labeling anal. showed that inhibition of HDAC3 resulted in a significant redn. in DNA replication fork velocity within the first hour of drug treatment. These results suggest that selective inhibition of HDAC3 could be useful in treatment of CTCL by disrupting DNA replication of the rapidly cycling tumor cells, ultimately leading to cell death.
- 190Gupta, M.; Han, J. J.; Stenson, M.; Wellik, L.; Witzig, T. E. Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapy. Leukemia 2012, 26, 1356– 1364, DOI: 10.1038/leu.2011.340[Crossref], [PubMed], [CAS], Google Scholar190https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xot1emt74%253D&md5=639b2827411ad5b4c3ba31c16568b961Regulation of STAT3 by histone deacetylase-3 in diffuse large B-cell lymphoma: implications for therapyGupta, M.; Han, J. J.; Stenson, M.; Wellik, L.; Witzig, T. E.Leukemia (2012), 26 (6), 1356-1364CODEN: LEUKED; ISSN:0887-6924. (Nature Publishing Group)Diffuse large B-cell lymphoma (DLBCL) with an activated B-cell (ABC) gene-expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B-cell type. ABC cell lines have constitutive activation of STAT3; however, the mechanisms regulating STAT3 signaling in lymphoma are unknown. In studies of class-I histone deacetylase (HDAC) expression, we found overexpression of HDAC3 in phospho STAT3-pos. DLBCL and the HDAC3 was found to be complexed with STAT3. Inhibition of HDAC activity by panobinostat (LBH589) increased p300-mediated STAT3Lys685 acetylation with increased nuclear export of STAT3 to the cytoplasm. HDAC inhibition abolished STAT3Tyr705 phosphorylation with minimal effect on STAT3Ser727 and JAK2 tyrosine activity. pSTAT3Tyr705-pos. DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3Tyr705-neg. DLBCLs. This cytotoxicity was assocd. with downregulation of the direct STAT3 target Mcl-1. HDAC3 knockdown upregulated STAT3Lys685 acetylation but prevented STAT3Tyr705 phosphorylation and inhibited survival of pSTAT3-pos. DLBCL cells. These studies provide the rationale for targeting STAT3-pos. DLBCL tumors with HDAC inhibitors.
- 191Narita, N.; Fujieda, S.; Tokuriki, M.; Takahashi, N.; Tsuzuki, H.; Ohtsubo, T.; Matsumoto, H. Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer. Oncogene 2005, 24, 7346– 7354, DOI: 10.1038/sj.onc.1208879[Crossref], [PubMed], [CAS], Google Scholar191https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXhtF2ns7%252FI&md5=c3046947f2fc5b18ef1ae1142e1f24e4Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancerNarita, Norihiko; Fujieda, Shigeharu; Tokuriki, Masaharu; Takahashi, Noboru; Tsuzuki, Hideaki; Ohtsubo, Toshio; Matsumoto, HidekiOncogene (2005), 24 (49), 7346-7354CODEN: ONCNES; ISSN:0950-9232. (Nature Publishing Group)To elucidate the mol. mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 44° for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcription-polymerase chain reaction (RT-PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 44° for 30 min at pH 6.7. Although the cytotoxicity of heating at 44° for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G2/M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G2/M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 43° for 30 min in vivo. Analyses of p65 activity suggested that NF-κB is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.
- 192Ho, M.; Chen, T.; Liu, J.; Dowling, P.; Hideshima, T.; Zhang, L.; Morelli, E.; Camci-Unal, G.; Wu, X.; Tai, Y. T.; Wen, K.; Samur, M.; Schlossman, R. L.; Mazitschek, R.; Kavanagh, E. L.; Lindsay, S.; Harada, T.; McCann, A.; Anderson, K. C.; O’Gorman, P.; Bianchi, G. Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling. Leukemia 2020, 34, 196– 209, DOI: 10.1038/s41375-019-0493-x[Crossref], [PubMed], [CAS], Google Scholar192https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhtVyqs7bE&md5=27482093e7a20546132cf4a18ab409d5Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signalingHo, Matthew; Chen, Tianzeng; Liu, Jiye; Dowling, Paul; Hideshima, Teru; Zhang, Li; Morelli, Eugenio; Camci-Unal, Gulden; Wu, Xinchen; Tai, Yu-Tzu; Wen, Kenneth; Samur, Mehmet; Schlossman, Robert L.; Mazitschek, Ralph; Kavanagh, Emma L.; Lindsay, Sinead; Harada, Takeshi; McCann, Amanda; Anderson, Kenneth C.; O'Gorman, Peter; Bianchi, GiadaLeukemia (2020), 34 (1), 196-209CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacol. inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quant. and qual. changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as mol. mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clin. development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment.
- 193Zhang, L.; Hong, Z.; Zhang, R. R.; Sun, X. Z.; Yuan, Y. F.; Hu, J.; Wang, X. Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways. Biomed. Pharmacother. 2016, 83, 958– 966, DOI: 10.1016/j.biopha.2016.07.049[Crossref], [PubMed], [CAS], Google Scholar193https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhsVWmtrzJ&md5=42cfc771b7a353471bb349cbe1bc0767Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathwaysZhang, Lei; Hong, Ze; Zhang, Rong-rong; Sun, Xing-zhen; Yuan, Yu-fang; Hu, Jian; Wang, XiangBiomedicine & Pharmacotherapy (2016), 83 (), 958-966CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Leukemia has been the third type of cancer killing many people across the world. Bakkenolide A (Bak), extd. from Petasites tricholobus, has been suggested to against cancer and display protective effects on inflammatory cytokines formation. And increasing evidences suggest that histone deacetylase 3 (HDAC3) plays vital roles in cancer formation and persistence via cell death, apoptosis and inflammation. But the function of Bakkenolide A in regulating leukemia is not understood yet, particularly via HDAC3. Here, we found that HDAC3 is up-regulated in clin. samples of leukemia compared with adjacent normal tissues. Then the expression of HDAC3 was knocked down via RNA interference in K562 cells. And inhibition of HDAC3 expression is able to improve leukemia invasion, migration and proliferation. Further, we also found HDAC3 bound to IκBα, affecting subsequent inflammation response. Moreover, Bakkenolide A was found to inhibit inflammation, induce apoptosis and cell death in leukemia cells via PI3K-regulated signaling pathway, down-regulating IKKs expression and suppressing in proinflammatory cytokines of IL-1β, IL-18 and TNF-α. Up-regulation of Caspase3/7 was obsd. in cells of HDAC3-knockdown and Bakkenolide A treatment, inducing leukemia cell apoptosis. Also, the expression of Akt and GSK were activated by HDAC3-knockdown and Bakkenolide A-treatment. Thus, these results indicated that Bakkenolide A-mediated HDAC3 sensitization in leukemia cells seem to be assocd. with activation of effector IKKs, Akt/GSK, and caspases through induction of the PI3K pathway, leading to inflammation, cell death, and apoptosis.
- 194Yan, Y.; An, J.; Yang, Y.; Wu, D.; Bai, Y.; Cao, W.; Ma, L.; Chen, J.; Yu, Z.; He, Y.; Jin, X.; Pan, Y.; Ma, T.; Wang, S.; Hou, X.; Weroha, S. J.; Karnes, R. J.; Zhang, J.; Westendorf, J. J.; Wang, L.; Chen, Y.; Xu, W.; Zhu, R.; Wang, D.; Huang, H. Dual inhibition of AKT-mTOR and AR signaling by targeting HDAC3 in PTEN- or SPOP-mutated prostate cancer. EMBO Mol. Med. 2018, 10, e8478 DOI: 10.15252/emmm.201708478
- 195Xu, Y.; Voelter-Mahlknecht, S.; Mahlknecht, U. The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell lines. Int. J. Mol. Med. 2005, 15, 169– 172[PubMed], [CAS], Google Scholar195https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXmsFeiug%253D%253D&md5=b3d836b7b2cf1edb5c85a3aa43672c50The histone deacetylase inhibitor suberoylanilide hydroxamic acid down-regulates expression levels of Bcr-abl, c-Myc and HDAC3 in chronic myeloid leukemia cell linesXu, Yaoxian; Voelter-Mahlknecht, Susanne; Mahlknecht, UlrichInternational Journal of Molecular Medicine (2005), 15 (1), 169-172CODEN: IJMMFG; ISSN:1107-3756. (International Journal of Molecular Medicine)In chronic myelocytic leukemia (CML) the activity of the Bcr-Abl tyrosine kinase is known to activate a no. of mol. mechanisms,, which inhibit apoptosis. In the present study, we show that the histone deacetylase inhibitor SARA (suberoylanilide hydroxamic acid) markedly decreases protein expression levels of Bcr-Abl and c-Myc in BV-173 cells, while in K562 cells only a minor decrease of Bcr-Abl protein levels is obsd. while a considerable redn. of c-Myc protein expression may only be achieved at higher concns. of SAHA. In addn., we found BV-173 cells to be more sensitive to SAHA-induced apoptosis when compared to K562 cells. Even though earlier reports on SAHA considerably focused on its inhibitory effect on HDAC enzymic activity, we report herein a significant downregulation of HDAC3 protein expression levels following treatment with SAHA in BV-173 cells, but not in K562 cells. In conclusion, our results imply a mol. mechanism for SAHA-induced apoptosis in BV-173 cells, which involves decreased protein expression levels of Bcr-Abl, c-Myc and HDAC3.
- 196Harada, T.; Ohguchi, H.; Grondin, Y.; Kikuchi, S.; Sagawa, M.; Tai, Y. T.; Mazitschek, R.; Hideshima, T.; Anderson, K. C. HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implications. Leukemia 2017, 31, 2670– 2677, DOI: 10.1038/leu.2017.144[Crossref], [PubMed], [CAS], Google Scholar196https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtVCiurfJ&md5=1bd7e215aa417f78eb0b51ac0c482144HDAC3 regulates DNMT1 expression in multiple myeloma: therapeutic implicationsHarada, T.; Ohguchi, H.; Grondin, Y.; Kikuchi, S.; Sagawa, M.; Tai, Y.-T.; Mazitschek, R.; Hideshima, T.; Anderson, K. C.Leukemia (2017), 31 (12), 2670-2677CODEN: LEUKED; ISSN:0887-6924. (Nature Research)Epigenetic signaling pathways are implicated in tumorigenesis and therefore histone deacetylases (HDACs) represent novel therapeutic targets for cancers, including multiple myeloma (MM). Although non-selective HDAC inhibitors show anti-MM activities, unfavorable side effects limit their clin. efficacy. Isoform- and/or class-selective HDAC inhibition offers the possibility to maintain clin. activity while avoiding adverse events attendant to broad non-selective HDAC inhibition. We have previously reported that HDAC3 inhibition, either by genetic knockdown or selective inhibitor BG45, abrogates MM cell proliferation. Here we show that knockdown of HDAC3, but not HDAC1 or HDAC2, as well as BG45, downregulate expression of DNA methyltransferase 1 (DNMT1) mediating MM cell proliferation. DNMT1 expression is regulated by c-Myc, and HDAC3 inhibition triggers degrdn. of c-Myc protein. Moreover, HDAC3 inhibition results in hyperacetylation of DNMT1, thereby reducing the stability of DNMT1 protein. Combined inhibition of HDAC3 and DNMT1 with BG45 and DNMT1 inhibitor 5-azacytidine (AZA), resp., triggers synergistic downregulation of DNMT1, growth inhibition and apoptosis in both MM cell lines and patient MM cells. Efficacy of this combination treatment is confirmed in a murine xenograft MM model. Our results therefore provide the rationale for combination treatment using HDAC3 inhibitor with DNMT1 inhibitor to improve patient outcome in MM.
- 197Lombard, D. B.; Cierpicki, T.; Grembecka, J. Combined MAPK pathway and HDAC inhibition breaks melanoma. Cancer Discovery 2019, 9, 469– 471, DOI: 10.1158/2159-8290.CD-19-0069[Crossref], [PubMed], [CAS], Google Scholar197https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhslKksLzP&md5=442f8bd62e83ea5968c9a4e503c6e9b2Combined MAPK pathway and HDAC inhibition breaks melanomaLombard, David B.; Cierpicki, Tomasz; Grembecka, JolantaCancer Discovery (2019), 9 (4), 469-471CODEN: CDAIB2; ISSN:2159-8274. (American Association for Cancer Research)A review. In this issue, Maertens and colleagues demonstrate that HDAC3 inhibition potentiates the effects of MAPK pathway inhibitors in melanoma, including difficult-to-treat NRAS- and NF1-driven tumors, with MGMT expression serving as a biomarker for responsiveness to the BRAF/MEK/HDAC inhibitor combination. Mechanistically, this triple cocktail suppresses expression of genes involved in DNA repair, leading to enhanced killing of melanoma cells.
- 198Escaffit, F.; Vaute, O.; Chevillard-Briet, M.; Segui, B.; Takami, Y.; Nakayama, T.; Trouche, D. Cleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progression. Mol. Cell. Biol. 2007, 27, 554– 567, DOI: 10.1128/MCB.00869-06[Crossref], [PubMed], [CAS], Google Scholar198https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXmvVOmuw%253D%253D&md5=577bb1dfd418ae9c06ec7760af1dc18bCleavage and cytoplasmic relocalization of histone deacetylase 3 are important for apoptosis progressionEscaffit, Fabrice; Vaute, Olivier; Chevillard-Briet, Martine; Segui, Bruno; Takami, Yasunari; Nakayama, Tatsuo; Trouche, DidierMolecular and Cellular Biology (2007), 27 (2), 554-567CODEN: MCEBD4; ISSN:0270-7306. (American Society for Microbiology)The histone deacetylase 3 (HDAC-3), which is a known corepressor of many proapoptotic genes, is subjected to proteolytic cleavage during apoptosis in a cell type- and species-independent manner. This cleavage is caspase dependent and leads to the loss of the C-terminal part of HDAC-3. The cleaved form of HDAC-3 accumulates in the cytoplasm. Furthermore, we found that forced nuclear localization of HDAC-3 decreases the efficiency of apoptosis induction, indicating that HDAC-3 cytoplasmic relocalization is important for the apoptotic process. Finally, we obsd. that HDAC-3 cleavage allowed increased histone acetylation and transcriptional activation on a proapoptotic HDAC-3-target gene, the Fas-encoding gene. Altogether, our results thus indicate that HDAC-3 cleavage is crucial for efficient apoptosis induction because it allows the activation of some proapoptotic genes during apoptosis progression.
- 199Xia, Y.; Wang, J.; Liu, T. J.; Yung, W. K.; Hunter, T.; Lu, Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol. Cell 2007, 25, 219– 232, DOI: 10.1016/j.molcel.2007.01.005[Crossref], [PubMed], [CAS], Google Scholar199https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhslKjurY%253D&md5=d162c146b04311b1e4e88e3dadf48561c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosisXia, Yan; Wang, Ji; Liu, Ta-Jen; Yung, W. K. Alfred; Hunter, Tony; Lu, ZhiminMolecular Cell (2007), 25 (2), 219-232CODEN: MOCEFL; ISSN:1097-2765. (Cell Press)C-Jun, a major transcription factor in the activating protein 1 (AP-1) family of regulatory proteins, is activated by many physiol. and pathol. stimuli. However, whether c-jun is regulated by epigenetic modification of chromatin structure is not clear. We showed here that c-jun was transcriptionally repressed in response to osmotic stress via a truncated HDAC3 generated by caspase-7-dependent cleavage at aspartic acid 391. The activation of caspase-7, which is independent of cytochrome c release and activation of caspase-9 and caspase-12, depends on activation of caspase-8, which in turn requires MEK2 activity and secretion of FAS ligand. The cell apoptosis induced by the truncated HDAC3 or enhanced by c-Jun deficiency during osmotic stress was suppressed by exogenous expression of c-Jun, indicating that the downregulation of c-Jun by HDAC3-dependent transcriptional repression plays a role in regulating cell survival and apoptosis.
- 200He, P.; Li, K.; Li, S. B.; Hu, T. T.; Guan, M.; Sun, F. Y.; Liu, W. W. Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancer. Int. J. Oncol. 2018, 52, 1305– 1316, DOI: 10.3892/ijo.2018.4284[Crossref], [PubMed], [CAS], Google Scholar200https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXitFOqsLbL&md5=d072b6ca93d15bd16138b4efce99f6b7Upregulation of AKAP12 with HDAC3 depletion suppresses the progression and migration of colorectal cancerHe, Ping; Li, Ke; Li, Shi-Bao; Hu, Ting-Ting; Guan, Ming; Sun, Fen-Yong; Liu, Wei-WeiInternational Journal of Oncology (2018), 52 (4), 1305-1316CODEN: IJONES; ISSN:1791-2423. (Spandidos Publications Ltd.)A-kinase anchor protein 12 (AKAP12; also known as Gravin) functions as a tumor suppressor in several human primary cancers. However, the potential correlation between histone deacetylase 3 (HDAC3) and AKAP12 and the underlying mechanisms remain unclear. Thus, in this study, in an aim to shed light into this matter, the expression levels of HDAC3 and AKAP12 in 96 colorectal cancer (CRC) and adjacent noncancerous tissues, as well as in SW480 cells were examd. by immunohistochem., RT-qPCR and western blot analyses. The effects of HDAC3 and AKAP12 on the proliferation, apoptosis and metastasis of CRC cells were examd. by cell counting kit-8 (CCK-8) assay, colony formation assays, flow cytometry, cell cycle anal. and Transwell assays. The results revealed that the redn. or loss of AKAP12 expression was detected in 69 (71.8%) of the 96 tissue specimens, whereas HDAC3 was upregulated in 50 (52.1%) of the 96 tumor tissue specimens. AKAP12 expression was markedly increased upon treatment with the HDAC3 inhibitors, trichostatin A (TSA) and RGFP966, at both the mRNA and protein level. Mechanistically, the direct binding of HDAC3 within the intron-1 region of AKAP12 was identified to be indispensable for the inhibition of AKAP12 expression. Moreover, the proliferation, colony-forming ability, cell cycle progression and the migration of the CRC cells were found to be promoted in response to AKAP12 silencing or AKAP12/HDAC3 co-silencing, whereas transfection with si-HDAC3 yielded opposite effects. Apart from the elevated expression of the anti-apoptotic protein, Bcl-2, after AKAP12 knockdown, the increased activity of PI3K/AKT signaling was found to be indispensable for AKAP12-mediated colony formation and migration. On the whole, these findings indicate that AKAP12 may be a potential prognostic predictor and therapeutic target for the treatment of CRC in combination with HDAC3.
- 201Ma, Y.; Baltezor, M.; Rajewski, L.; Crow, J.; Samuel, G.; Staggs, V. S.; Chastain, K. M.; Toretsky, J. A.; Weir, S. J.; Godwin, A. K. Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axis. J. Mol. Med. (Heidelberg, Ger.) 2019, 97, 957– 962, DOI: 10.1007/s00109-019-01782-0[Crossref], [PubMed], [CAS], Google Scholar201https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXos12itbk%253D&md5=8c4c37d083b496d26a4df0a39317cd66Targeted inhibition of histone deacetylase leads to suppression of Ewing sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90 signaling axisMa, Yan; Baltezor, Michael; Rajewski, Lian; Crow, Jennifer; Samuel, Glenson; Staggs, Vincent S.; Chastain, Katherine M.; Toretsky, Jeffrey A.; Weir, Scott J.; Godwin, Andrew K.Journal of Molecular Medicine (Heidelberg, Germany) (2019), 97 (7), 957-972CODEN: JMLME8; ISSN:0946-2716. (Springer)Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 mo of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clin. benefit, thereby emphasizing a clin. responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclin. proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclin. ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, resp. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clin. development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. Entinostat potently inhibits ES both in vitro and in vivo. · EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. · Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. · HDAC3 is a transcriptional target of EWS-FLI1. · HDAC3 is essential for ES cell viability and genomic stability maintenance.
- 202Zeng, Z.; Liao, R.; Yao, Z.; Zhou, W.; Ye, P.; Zheng, X.; Li, X.; Huang, Y.; Chen, S.; Chen, Q. Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: a community-based case-control study. Gene 2014, 533, 427– 433, DOI: 10.1016/j.gene.2013.09.123[Crossref], [PubMed], [CAS], Google Scholar202https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhs1yhsbzM&md5=842d6b57b0fdf499306d12d7ad456fe6Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: A community-based case-control studyZeng, Zhuanping; Liao, Rifang; Yao, Zhenjiang; Zhou, Weiping; Ye, Ping; Zheng, Xueyan; Li, Xing; Huang, Yanhui; Chen, Sidong; Chen, QingGene (2014), 533 (1), 427-433CODEN: GENED6; ISSN:0378-1119. (Elsevier B.V.)There are no data regarding the possible role of the single nucleotide polymorphism (SNP) of class I histone deacetylases (HDACs) in type 2 diabetes mellitus (DM). We designed this study to examine whether polymorphisms of HDACs can be implicated in that disease. A community-based, case-control study was conducted, with a total of 568 subjects (284 patients and 284 controls) enrolled. Four polymorphisms of HDAC1 (rs1741981) and HDAC3 (rs11741808, rs2547547, rs2530223) were examd. by the use of TaqMan technol. We found a significant assocn. with risk of type 2 DM for three SNPs of HDAC3, including rs11741808 [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.35-0.81], rs2547547 [OR = 1.72, 95% CI: 1.13-2.64], and rs2530223 [OR = 1.39; 95% CI: 1.01-1.91]. Subgroup anal. showed that BMI ≥ 23 kg/m2, high triglyceride and high blood pressure, together with the rs11741808AG genotype, were assocd. with a significantly decreased risk for type 2 DM, with ORs of 0.50 (95% CI: 0.27-0.91), 0.38 (95% CI: 0.20-0.71) and 0.43 (95% CI: 0.24-0.76) compared with the AA genotype, resp. In a population with normal total cholesterol, the AG genotype yielded a significantly decreased risk of type 2 DM risk, with an OR of 0.42 (95% CI: 0.25-0.70) when compared with the persons of the AA genotype. For rs2547547, in a population with normal total cholesterol and triglyceride, the AG genotype was assocd. with a significantly increased risk of type 2 DM, with ORs of 1.92 (95% CI: 1.17-3.15) and 2.24 (95% CI: 1.28-3.94) when compared with the population carrying the AA genotype. The results suggest that variants of HDAC3 contribute to an increased prevalence of type 2 DM in the Chinese Han population.
- 203Lundh, M.; Galbo, T.; Poulsen, S. S.; Mandrup-Poulsen, T. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats. Diabetes, Obes. Metab. 2015, 17, 703– 707, DOI: 10.1111/dom.12470[Crossref], [PubMed], [CAS], Google Scholar203https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtVOnur3I&md5=ce9b1112670b4e3b07ffce66f1ba8b38Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic ratsLundh, M.; Galbo, T.; Poulsen, S. S.; Mandrup-Poulsen, T.Diabetes, Obesity and Metabolism (2015), 17 (7), 703-707CODEN: DOMEF6; ISSN:1462-8902. (Wiley-Blackwell)Failure of pancreatic β cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to β-cell failure. Selective inhibition of histone deacetylase (HDAC)-3 protects pancreatic β cells against inflammatory and metabolic insults in vitro. In the present study, we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycemia and increase insulin secretion in a rat model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycemic clamp was performed. HDAC3 inhibition improved hyperglycemia over the study period without affecting wt. gain. At the end of the hyperglycemic clamp, circulating insulin levels were significantly higher in BRD3308-treated rats. Pancreatic insulin staining and contents were also significantly higher. These findings highlight HDAC3 as a key therapeutic target for β-cell protection in type 2 diabetes.
- 204Wagner, F. F.; Lundh, M.; Kaya, T.; McCarren, P.; Zhang, Y. L.; Chattopadhyay, S.; Gale, J. P.; Galbo, T.; Fisher, S. L.; Meier, B. C.; Vetere, A.; Richardson, S.; Morgan, N. G.; Christensen, D. P.; Gilbert, T. J.; Hooker, J. M.; Leroy, M.; Walpita, D.; Mandrup-Poulsen, T.; Wagner, B. K.; Holson, E. B. An isochemogenic set of inhibitors to define the therapeutic potential of histone deacetylases in β-cell protection. ACS Chem. Biol. 2016, 11, 363– 374, DOI: 10.1021/acschembio.5b00640[ACS Full Text], [CAS], Google Scholar204https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtVCnsL4%253D&md5=0d57ffcfc229ec4efe3857882ff9113eAn Isochemogenic Set of Inhibitors To Define the Therapeutic Potential of Histone Deacetylases in β-Cell ProtectionWagner, Florence F.; Lundh, Morten; Kaya, Taner; McCarren, Patrick; Zhang, Yan-Ling; Chattopadhyay, Shrikanta; Gale, Jennifer P.; Galbo, Thomas; Fisher, Stewart L.; Meier, Bennett C.; Vetere, Amedeo; Richardson, Sarah; Morgan, Noel G.; Christensen, Dan Ploug; Gilbert, Tamara J.; Hooker, Jacob M.; Leroy, Melanie; Walpita, Deepika; Mandrup-Poulsen, Thomas; Wagner, Bridget K.; Holson, Edward B.ACS Chemical Biology (2016), 11 (2), 363-374CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)Modulation of histone deacetylase (HDAC) activity has been implicated as a potential therapeutic strategy for multiple diseases. However, it has been difficult to dissect the role of individual HDACs due to a lack of selective small-mol. inhibitors. Here, we report the synthesis of a series of highly potent and isoform-selective class I HDAC inhibitors, rationally designed by exploiting minimal structural changes to the clin. experienced HDAC inhibitor CI-994. We used this toolkit of isochemogenic or chem. matched inhibitors to probe the role of class I HDACs in β-cell pathobiol. and demonstrate for the first time that selective inhibition of an individual HDAC isoform retains beneficial biol. activity and mitigates mechanism-based toxicities. The highly selective HDAC3 inhibitor BRD3308 suppressed pancreatic β-cell apoptosis induced by inflammatory cytokines, as expected, or now glucolipotoxic stress, and increased functional insulin release. In addn., BRD3308 had no effect on human megakaryocyte differentiation, while inhibitors of HDAC1 and 2 were toxic. Our findings demonstrate that the selective inhibition of HDAC3 represents a potential path forward as a therapy to protect pancreatic β-cells from inflammatory cytokines and nutrient overload in diabetes.
- 205Ye, J. Improving insulin sensitivity with HDAC inhibitor. Diabetes 2013, 62, 685– 687, DOI: 10.2337/db12-1354[Crossref], [PubMed], [CAS], Google Scholar205https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsFGrt7g%253D&md5=001cf6dbd06237bdc3cee19f54aeb9baImproving insulin sensitivity with HDAC inhibitorYe, JianpingDiabetes (2013), 62 (3), 685-687CODEN: DIAEAZ; ISSN:0012-1797. (American Diabetes Association, Inc.)A review. The research of Galmozzi et al. (2013) entitled 'Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metab. in skeletal muscle and adipose tissue' is reviewed with commentary and refs. The study by these authors provides new insight into the distinction between class I and class II inhibitors in regulation of insulin sensitivity. Their results showed that class I histone deacetylase inhibitors (HDACi) enhanced whole-body energy expenditure, improved insulin sensitivity, and stimulated oxidative phosphorylation and mitochondrial function in the muscle and fat of mice. The mechanism was attributed to induction of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α. In contrast, class II HDACi did not exhibit these actions, suggesting that class I HDACi are more important in the regulation of energy metab. and insulin sensitivity. Despite these interesting new findings, these data should be interpreted with caution.
- 206Gao, Z.; He, Q.; Peng, B.; Chiao, P. J.; Ye, J. Regulation of nuclear translocation of HDAC3 by IkappaBalpha is required for tumor necrosis factor inhibition of peroxisome proliferator-activated receptor gamma function. J. Biol. Chem. 2006, 281, 4540– 4547, DOI: 10.1074/jbc.M507784200[Crossref], [PubMed], [CAS], Google Scholar206https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XhtlKrs78%253D&md5=6f143e89f1279e7846e3b02196f41bfdRegulation of Nuclear Translocation of HDAC3 by IκBα Is Required for Tumor Necrosis Factor Inhibition of Peroxisome Proliferator-activated Receptor γ FunctionGao, Zhanguo; He, Qing; Peng, Bailu; Chiao, Paul J.; Ye, JianpingJournal of Biological Chemistry (2006), 281 (7), 4540-4547CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Inhibition of peroxisome proliferator-activated receptor γ (PPARγ) function by TNF-α contributes to glucose and fatty acid metabolic disorders in inflammation and cancer, although the mol. mechanism is not fully understood. In this study, the authors demonstrate that nuclear translocation of HDAC3 is regulated by TNF-α, and this event is required for inhibition of transcriptional activity of PPARγ by TNF-α. HDAC3 is assocd. with IκBα in the cytoplasm. After IκBα degrdn. in response to TNF-α, HDAC3 is subject to nuclear translocation, leading to an increase in HDAC3 activity in the nucleus. This event leads to subcellular redistribution of HDAC3. Knock-out of IκBα, but not p65 or p50, leads to disappearance of HDAC3 in the cytoplasm, which is assocd. with HDAC3 enrichment in the nucleus. These data suggest that inhibition of PPARγ by TNF-α is not assocd. with a redn. in the DNA binding activity of PPARγ. Rather, these results suggest that IκBα-dependent nuclear translocation of HDAC3 is responsible for PPARγ inhibition by TNF-α.
- 207Jiang, X.; Ye, X.; Guo, W.; Lu, H.; Gao, Z. Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation. J. Mol. Endocrinol. 2014, 53, 191– 200, DOI: 10.1530/JME-14-0066[Crossref], [PubMed], [CAS], Google Scholar207https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC2cfotFGmsQ%253D%253D&md5=b60551a5092649169e960beaa3509ebbInhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylationJiang Xiaoting; Ye Xin; Guo Wei; Lu Hongyun; Gao ZhanguoJournal of molecular endocrinology (2014), 53 (2), 191-200 ISSN:.Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.
- 208Chou, D. H.; Holson, E. B.; Wagner, F. F.; Tang, A. J.; Maglathlin, R. L.; Lewis, T. A.; Schreiber, S. L.; Wagner, B. K. Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis. Chem. Biol. 2012, 19, 669– 673, DOI: 10.1016/j.chembiol.2012.05.010[Crossref], [PubMed], [CAS], Google Scholar208https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XptVKrsL4%253D&md5=47153de783321575c2f5606f16d28bb8Inhibition of Histone Deacetylase 3 Protects Beta Cells from Cytokine-Induced ApoptosisChou, Danny Hung-Chieh; Holson, Edward B.; Wagner, Florence F.; Tang, Alicia J.; Maglathlin, Rebecca L.; Lewis, Timothy A.; Schreiber, Stuart L.; Wagner, Bridget K.Chemistry & Biology (Oxford, United Kingdom) (2012), 19 (6), 669-673CODEN: CBOLE2; ISSN:1074-5521. (Elsevier Ltd.)Cytokine-induced beta-cell apoptosis is important to the etiol. of type-1 diabetes. Although previous reports have shown that general inhibitors of histone deacetylase (HDAC) activity, such as suberoylanilide hydroxamic acid and trichostatin A, can partially prevent beta-cell death, they do not fully restore beta-cell function. To understand HDAC isoform selectivity in beta cells, we measured the cellular effects of 11 structurally diverse HDAC inhibitors on cytokine-induced apoptosis in the rat INS-1E cell line. All 11 compds. restored ATP levels and reduced nitrite secretion. However, caspase-3 activity was reduced only by MS-275 and CI-994, both of which target HDAC1, 2, and 3. Importantly, both MS-275 and genetic knockdown of Hdac3 alone were sufficient to restore glucose-stimulated insulin secretion in the presence of cytokines. These results suggest that HDAC3-selective inhibitors may be effective in preventing cytokine-induced beta-cell apoptosis.
- 209Xu, Z.; Tong, Q.; Zhang, Z.; Wang, S.; Zheng, Y.; Liu, Q.; Qian, L. B.; Chen, S. Y.; Sun, J.; Cai, L. Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway. Clin. Sci. 2017, 131, 1841– 1857, DOI: 10.1042/CS20170064[Crossref], [CAS], Google Scholar209https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Wrs73K&md5=686f184cf3ae5e901b6e7dfd35680eabInhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathwayXu, Zheng; Tong, Qian; Zhang, Zhiguo; Wang, Shudong; Zheng, Yang; Liu, Qiuju; Qian, Ling-bo; Chen, Shao-yu; Sun, Jian; Cai, LuClinical Science (2017), 131 (15), 1841-1857CODEN: CSCIAE; ISSN:1470-8736. (Portland Press Ltd.)Inhibition of total histone deacetylases (HDACs) was phenomenally assocd. with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to det. whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevents DCM. Type 1 diabetes OVE26 and age-matched wild-type (WT) mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 mo. These mice were then killed immediately or 3 mo later for cardiac function and pathol. examn. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice killed immediately or 3 mo later following the 3-mo treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunopptn. (ChIP) assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. The present study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.
- 210Dávalos-Salas, M.; Montgomery, M. K.; Reehorst, C. M.; Nightingale, R.; Ng, I.; Anderton, H.; Al-Obaidi, S.; Lesmana, A.; Scott, C. M.; Ioannidis, P.; Kalra, H.; Keerthikumar, S.; Tögel, L.; Rigopoulos, A.; Gong, S. J.; Williams, D. S.; Yoganantharaja, P.; Bell-Anderson, K.; Mathivanan, S.; Gibert, Y.; Hiebert, S.; Scott, A. M.; Watt, M. J.; Mariadason, J. M. Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity. Nat. Commun. 2019, 10, 5219, DOI: 10.1038/s41467-019-13180-8
- 211Knutson, S. K.; Chyla, B. J.; Amann, J. M.; Bhaskara, S.; Huppert, S. S.; Hiebert, S. W. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J. 2008, 27, 1017– 1028, DOI: 10.1038/emboj.2008.51[Crossref], [PubMed], [CAS], Google Scholar211https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXksVagurs%253D&md5=eefeb4f059e6cbbbb176d8d8c3d93462Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networksKnutson, Sarah K.; Chyla, Brenda J.; Amann, Joseph M.; Bhaskara, Srividya; Huppert, Stacey S.; Hiebert, Scott W.EMBO Journal (2008), 27 (7), 1017-1028CODEN: EMJODG; ISSN:0261-4189. (Nature Publishing Group)Histone deacetylase 3 (Hdac3) is an enzymic component of transcriptional repression complexes recruited by the nuclear hormone receptors. Inactivation of Hdac3 in cancer cell lines triggered apoptosis, and removal of Hdac3 in the germ line of mice caused embryonic lethality. Therefore, we deleted Hdac3 in the postnatal mouse liver. These mice developed hepatomegaly, which was the result of hepatocyte hypertrophy, and these morphol. changes coincided with significant imbalances between carbohydrate and lipid metab. Loss of Hdac3 triggered changes in gene expression consistent with inactivation of repression mediated by nuclear hormone receptors. Loss of Hdac3 also increased the levels of Pparγ2, and treatment of these mice with a Pparγ antagonist partially reversed the lipid accumulation in the liver. In addn., gene expression anal. identified mammalian target of rapamycin signaling as being activated after deletion of Hdac3, and inhibition by rapamycin affected the accumulation of neutral lipids in Hdac3-null livers. Thus, Hdac3 regulates metab. through multiple signaling pathways in the liver, and deletion of Hdac3 disrupts normal metabolic homeostasis.
- 212Sun, Z.; Miller, R. A.; Patel, R. T.; Chen, J.; Dhir, R.; Wang, H.; Zhang, D.; Graham, M. J.; Unterman, T. G.; Shulman, G. I.; Sztalryd, C.; Bennett, M. J.; Ahima, R. S.; Birnbaum, M. J.; Lazar, M. A. Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestration. Nat. Med. 2012, 18, 934– 942, DOI: 10.1038/nm.2744[Crossref], [PubMed], [CAS], Google Scholar212https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XmsFOqsLw%253D&md5=30f561509e16f7550ec6ff0acd264654Hepatic Hdac3 promotes gluconeogenesis by repressing lipid synthesis and sequestrationSun, Zheng; Miller, Russell A.; Patel, Rajesh T.; Chen, Jie; Dhir, Ravindra; Wang, Hong; Zhang, Dongyan; Graham, Mark J.; Unterman, Terry G.; Shulman, Gerald I.; Sztalryd, Carole; Bennett, Michael J.; Ahima, Rexford S.; Birnbaum, Morris J.; Lazar, Mitchell A.Nature Medicine (New York, NY, United States) (2012), 18 (6), 934-942CODEN: NAMEFI; ISSN:1078-8956. (Nature Publishing Group)Fatty liver disease is assocd. with obesity and type 2 diabetes, and hepatic lipid accumulation may contribute to insulin resistance. Histone deacetylase 3 (Hdac3) controls the circadian rhythm of hepatic lipogenesis. Here we show that, despite severe hepatosteatosis, mice with liver-specific depletion of Hdac3 have higher insulin sensitivity without any changes in insulin signaling or body wt. compared to wild-type mice. Hdac3 depletion reroutes metabolic precursors towards lipid synthesis and storage within lipid droplets and away from hepatic glucose prodn. Perilipin 2, which coats lipid droplets, is markedly induced upon Hdac3 depletion and contributes to the development of both steatosis and improved tolerance to glucose. These findings suggest that the sequestration of hepatic lipids in perilipin 2-coated droplets ameliorates insulin resistance and establish Hdac3 as a pivotal epigenomic modifier that integrates signals from the circadian clock in the regulation of hepatic intermediary metab.
- 213Sun, Z.; Singh, N.; Mullican, S. E.; Everett, L. J.; Li, L.; Yuan, L.; Liu, X.; Epstein, J. A.; Lazar, M. A. Diet-induced lethality due to deletion of the Hdac3 gene in heart and skeletal muscle. J. Biol. Chem. 2011, 286, 33301– 33309, DOI: 10.1074/jbc.M111.277707[Crossref], [PubMed], [CAS], Google Scholar213https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXhtFOit7rP&md5=7b56dc884e4d811ba06e8ccb51f28363Diet-induced Lethality Due to Deletion of the Hdac3 Gene in Heart and Skeletal MuscleSun, Zheng; Singh, Nikhil; Mullican, Shannon E.; Everett, Logan J.; Li, Li; Yuan, Li-Jun; Liu, Xi; Epstein, Jonathan A.; Lazar, Mitchell A.Journal of Biological Chemistry (2011), 286 (38), 33301-33309, S33301/1-S33301/47CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Many human diseases result from the influence of the nutritional environment on gene expression. The environment interacts with the genome by altering the epigenome, including covalent modification of nucleosomal histones. Here, we report a novel and dramatic influence of diet on the phenotype and survival of mice in which histone deacetylase 3 (Hdac3) is deleted postnatally in heart and skeletal muscle. Although embryonic deletion of myocardial Hdac3 causes major cardiomyopathy that reduces survival, we found that excision of Hdac3 in heart and muscle later in development leads to a much milder phenotype and does not reduce survival when mice are fed normal chow. Remarkably, upon switching to a high fat diet, the mice begin to die within weeks and display signs of severe hypertrophic cardiomyopathy and heart failure. Down-regulation of myocardial mitochondrial bioenergetic genes, specifically those involved in lipid metab., precedes the full development of cardiomyopathy, suggesting that HDAC3 is important in maintaining proper mitochondrial function. These data suggest that loss of the epigenomic modifier HDAC3 causes dietary lethality by compromising the ability of cardiac mitochondria to respond to changes of nutritional environment. In addn., this study provides a mouse model for diet-inducible heart failure.
- 214Moumné, L.; Campbell, K.; Howland, D.; Ouyang, Y.; Bates, G. P. Genetic knock-down of HDAC3 does not modify disease-related phenotypes in a mouse model of Huntington’s disease. PLoS One 2012, 7, e31080 DOI: 10.1371/journal.pone.0031080[Crossref], [PubMed], [CAS], Google Scholar214https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XivVWiu7Y%253D&md5=c3cd65445b80fe8610c85ccd2503b88fGenetic knock-down of Hdac3 does not modify disease-related phenotypes in a mouse model of Huntington's diseaseMoumne, Lara; Campbell, Ken; Howland, David; Ouyang, Yingbin; Bates, Gillian P.PLoS One (2012), 7 (2), e31080CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder caused by an expansion of a CAG/polyglutamine repeat for which there are no disease modifying treatments. In recent years, transcriptional dysregulation has emerged as a pathogenic process that appears early in disease progression and has been recapitulated across multiple HD models. Altered histone acetylation has been proposed to underlie this transcriptional dysregulation and histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA), have been shown to improve polyglutamine-dependent phenotypes in numerous HD models. However potent pan-HDAC inhibitors such as SAHA display toxic side-effects. To better understand the mechanism underlying this potential therapeutic benefit and to dissoc. the beneficial and toxic effects of SAHA, we set out to identify the specific HDAC(s) involved in this process. For this purpose, we are exploring the effect of the genetic redn. of specific HDACs on HD-related phenotypes in the R6/2 mouse model of HD. The study presented here focuses on HDAC3, which, as a class I HDAC, is one of the preferred targets of SAHA and is directly involved in histone deacetylation. To evaluate a potential benefit of Hdac3 genetic redn. in R6/2, we generated a mouse carrying a crit. deletion in the Hdac3 gene. We confirmed that the complete knock-out of Hdac3 is embryonic lethal. To test the effects of HDAC3 inhibition, we used Hdac3+/- heterozygotes to reduce nuclear HDAC3 levels in R6/2 mice. We found that Hdac3 knock-down does not ameliorate physiol. or behavioral phenotypes and has no effect on mol. changes including dysregulated transcripts. We conclude that HDAC3 should not be considered as the major mediator of the beneficial effect induced by SAHA and other HDAC inhibitors in HD.
- 215Zhang, J.; Henagan, T. M.; Gao, Z.; Ye, J. Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammation. Endocrinology 2011, 152, 1829– 1838, DOI: 10.1210/en.2010-0828[Crossref], [PubMed], [CAS], Google Scholar215https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXmsVKqurk%253D&md5=b4a96a10328828168b2cb07f92a372e5Inhibition of glyceroneogenesis by histone deacetylase 3 contributes to lipodystrophy in mice with adipose tissue inflammationZhang, Jin; Henagan, Tara M.; Gao, Zhanguo; Ye, JianpingEndocrinology (2011), 152 (5), 1829-1838CODEN: ENDOAO; ISSN:0013-7227. (Endocrine Society)We have reported that the nuclear factor-κB (NF-κB) induces chronic inflammation in the adipose tissue of p65 transgenic (Tg) mice, in which the NF-κB subunit p65 (RelA) is overexpressed from the adipocyte protein 2 (aP2) gene promoter. Tg mice suffer a mild lipodystrophy and exhibit deficiency in adipocyte differentiation. To understand mol. mechanism of the defect in adipocytes, we investigated glyceroneogenesis by examg. the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) in adipocytes. In aP2-p65 Tg mice, Pepck expression is inhibited at both the mRNA and protein levels in adipose tissue. The mRNA redn. is a consequence of transcriptional inhibition but not alteration in mRNA stability. The Pepck gene promoter is inhibited by NF-κB, which enhances the corepressor activity through activation of histone deacetylase 3 (HDAC3) in the nucleus. HDAC3 suppresses Pepck transcription by inhibiting the transcriptional activators, peroxisome proliferator-activated receptor-γ, and cAMP response element binding protein. The NF-κB activity is abolished by Hdac3 knockdown or inhibition of HDAC3 catalytic activity. In a chromatin immunopptn. assay, HDAC3 interacts with peroxisome proliferator-activated receptor-γ and cAMP response element binding protein in the Pepck promoter when NF-κB is activated by TNF-α. These results suggest that HDAC3 mediates NF-κB activity to repress Pepck transcription. This mechanism is responsible for inhibition of glyceroneogenesis in adipocytes, which contributes to lipodystrophy in the aP2-p65 Tg mice.
- 216Schmitt, H. M.; Pelzel, H. R.; Schlamp, C. L.; Nickells, R. W. Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injury. Mol. Neurodegener. 2014, 9, 39, DOI: 10.1186/1750-1326-9-39[Crossref], [PubMed], [CAS], Google Scholar216https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVOmsA%253D%253D&md5=7fcd2b357933611c9c56473cca0b4c74Histone deacetylase 3 (HDAC3) plays an important role in retinal ganglion cell death after acute optic nerve injurySchmitt, Heather M.; Pelzel, Heather R.; Schlamp, Cassandra L.; Nickells, Robert W.Molecular Neurodegeneration (2014), 9 (), 39/1-39/15, 15 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Background: Optic nerve damage initiates a series of early atrophic events in retinal ganglion cells (RGCs) that precede the BAX-dependent committed step of the intrinsic apoptotic program. Nuclear atrophy, including global histone deacetylation, heterochromatin formation, shrinkage and collapse of nuclear structure, and the silencing of normal gene expression, comprise an important obstacle to overcome in therapeutic approaches to preserve neuronal function. Several studies have implicated histone deacetylases (HDACs) in the early stages of neuronal cell death, including RGCs. Importantly, these neurons exhibit nuclear translocation of HDAC3 shortly after optic nerve damage. Addnl., HDAC3 activity has been reported to be selectively toxic to neurons. Results: RGC-specific conditional knockout of Hdac3 was achieved by transducing the RGCs of Hdac3fl/fl mice with an adeno-assocd. virus serotype 2 carrying CRE recombinase and GFP (AAV2-Cre/GFP). Controls included similar viral transduction of Rosa26fl/fl reporter mice. Optic nerve crush (ONC) was then performed on eyes. The ablation of Hdac3 in RGCs resulted in significant amelioration of characteristics of ONC-induced nuclear atrophy such as H4 deacetylation, heterochromatin formation, and the loss of nuclear structure. RGC death was also significantly reduced. Interestingly, loss of Hdac3 expression did not lead to protection against RGC-specific gene silencing after ONC, although this effect was achieved using the broad spectrum inhibitor, Trichostatin A. Conclusion: Although other HDACs may be responsible for gene expression changes in RGCs, our results indicate a crit. role for HDAC3 in nuclear atrophy in RGC apoptosis following axonal injury. This study provides a framework for studying the roles of other prevalent retinal HDACs in neuronal death as a result of axonal injury.
- 217Schmitt, H. M.; Schlamp, C. L.; Nickells, R. W. Targeting HDAC3 activity with RGFP966 protects against retinal ganglion cell nuclear atrophy and apoptosis after optic nerve injury. J. Ocul. Pharmacol. Ther. 2018, 34, 260– 273, DOI: 10.1089/jop.2017.0059[Crossref], [PubMed], [CAS], Google Scholar217https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXntFWgs7w%253D&md5=a8b21a3a3afdc29f11b68d283cdfbc0bTargeting HDAC3 Activity with RGFP966 Protects Against Retinal Ganglion Cell Nuclear Atrophy and Apoptosis After Optic Nerve InjurySchmitt, Heather M.; Schlamp, Cassandra L.; Nickells, Robert W.Journal of Ocular Pharmacology and Therapeutics (2018), 34 (3), 260-273CODEN: JOPTFU; ISSN:1080-7683. (Mary Ann Liebert, Inc.)Purpose: HDAC3 regulates nuclear atrophy as an early response to axonal injury in retinal ganglion cells (RGCs) following optic nerve crush (ONC). Since conditional knockout of Hdac3 prevents nuclear atrophy post ONC, HDAC3 selective inhibition with RGFP966 through localized and systemic dosing of RGFP966 is necessary for application to acute and chronic models of optic nerve injury. Methods: C57BL/6 mice were injected intravitreally with 1-10μM RGFP966 immediately following ONC, and retinas were analyzed at 5, 7, and 14 days for metrics of nuclear atrophy and cell loss. Mice were similarly assessed after i.p. (IP) injections with RGFP966 doses of 2-10 mg/kg, and eyes were harvested at 5, 14, and 28 days after ONC. H&E and BrdU staining were used to analyze toxicity to off-target tissues after 14 days of daily treatment with RGFP966. Results: A single intravitreal injection of RGFP966 prevented histone deacetylation, heterochromatin formation, apoptosis, and DNA damage at 5 and 7 days post ONC. After IP injection, RGFP966 bioavailability in the retina reached peak concn. within 1 h after injection and then rapidly declined. A single IP injection of 2-10 mg/kg RGFP966, significantly prevented histone deacetylation. Repeated IP injections of 2 mg/kg RGFP966 over the course of 2 and 4 wk post ONC prevented RGC loss. There were no significant toxic or antiproliferative effects to off-target tissues in mice treated daily for 14 days with RGFP966. Conclusion: Inhibition of HDAC3 activity with systemic dosing of RGFP966 prevents apoptosis-related histone deacetylation and attenuates RGC loss after acute optic nerve injury.
- 218Norwood, J.; Franklin, J. M.; Sharma, D.; D’Mello, S. R. Histone deacetylase 3 is necessary for proper brain development. J. Biol. Chem. 2014, 289, 34569– 34582, DOI: 10.1074/jbc.M114.576397[Crossref], [PubMed], [CAS], Google Scholar218https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXlvVSnsA%253D%253D&md5=cb6d33ef429d400628e22220d2b8cf99Histone deacetylase 3 is necessary for proper brain developmentNorwood, Jordan; Franklin, Jade M.; Sharma, Dharmendra; D'Mello, Santosh R.Journal of Biological Chemistry (2014), 289 (50), 34569-34582, 15 pp.CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)The functional role of histone deacetylase 3 (HDAC3) in the developing brain has yet to be elucidated. We show that mice lacking HDAC3 in neurons and glia of the central nervous system, Nes-Cre/HDAC3 conditional KO mice, show major abnormalities in the cytoarchitecture of the neocortex and cerebellum and die within 24 h of birth. Later-born neurons do not localize properly in the cortex. A similar mislocalization is obsd. with cerebellar Purkinje neurons. Although the proportion of astrocytes is higher than normal, the nos. of oligodendrocytes are reduced. In contrast, conditional knockout of HDAC3 in neurons of the forebrain and certain other brain regions, using Thy1-Cre and calcium/calmodulin dependent protein kinase II α-Cre for ablation, produces no overt abnormalities in the organization of cells within the cortex or of cerebellar Purkinje neurons at birth. However, both lines of conditional knockout mice suffer from progressive hind limb paralysis and ataxia and die around 6 wk after birth. The mice display an increase in overall nos. of cells, higher nos. of astrocytes, and Purkinje neuron degeneration. Taken together, our results demonstrate that HDAC3 plays an essential role in regulating brain development, with effects on both neurons and glia in different brain regions.
- 219Herman, D.; Jenssen, K.; Burnett, R.; Soragni, E.; Perlman, S. L.; Gottesfeld, J. M. Histone deacetylase inhibitors reverse gene silencing in Friedreich’s ataxia. Nat. Chem. Biol. 2006, 2, 551– 558, DOI: 10.1038/nchembio815[Crossref], [PubMed], [CAS], Google Scholar219https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28Xps1aht7k%253D&md5=a4a3af8104d80260807087dcb5c3c178Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxiaHerman, David; Jenssen, Kai; Burnett, Ryan; Soragni, Elisabetta; Perlman, Susan L.; Gottesfeld, Joel M.Nature Chemical Biology (2006), 2 (10), 551-558, S551/1-S551/13CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)Expansion of GAA·TTC triplets within an intron in FXN (the gene encoding frataxin) leads to transcription silencing, forming the mol. basis for the neurodegenerative disease Friedreich's ataxia. Gene silencing at expanded FXN alleles is accompanied by hypoacetylation of histones H3 and H4 and trimethylation of histone H3 at Lys9, observations that are consistent with a heterochromatin-mediated repression mechanism. We describe the synthesis and characterization of a class of histone deacetylase (HDAC) inhibitors that reverse FXN silencing in primary lymphocytes from individuals with Friedreich's ataxia. We show that these mols. directly affect the histones assocd. with FXN, increasing acetylation at particular lysine residues on histones H3 and H4 (H3K14, H4K5 and H4K12). This class of HDAC inhibitors may yield therapeutics for Friedreich's ataxia.
- 220Xu, C.; Soragni, E.; Chou, C. J.; Herman, D.; Plasterer, H. L.; Rusche, J. R.; Gottesfeld, J. M. Chemical probes identify a role for histone deacetylase 3 in Friedreich’s Ataxia gene silencing. Chem. Biol. 2009, 16, 980– 989, DOI: 10.1016/j.chembiol.2009.07.010[Crossref], [PubMed], [CAS], Google Scholar220https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXhtFynsLrJ&md5=6157d7f06142b195ef686a540b459a28Chemical Probes Identify a Role for Histone Deacetylase 3 in Friedreich's Ataxia Gene SilencingXu, Chunping; Soragni, Elisabetta; Chou, C. James; Herman, David; Plasterer, Heather L.; Rusche, James R.; Gottesfeld, Joel M.Chemistry & Biology (Cambridge, MA, United States) (2009), 16 (9), 980-989CODEN: CBOLE2; ISSN:1074-5521. (Cell Press)We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chem. approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chem. addn. of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear ext. prepd. from human lymphoblasts with the trifunctional probe, followed by biotin addn. through click chem., streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Addnl. inhibitors with different HDAC specificity profiles were synthesized, and results from transcription expts. in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia.
- 221Xia, M. X.; Zhao, Q. C.; Zhang, H.; Chen, Y. T.; Yuan, Z. Q.; Xu, Y.; Zhang, M. J. Proteomic analysis of HDAC3 selective inhibitor in the regulation of inflammatory response of primary microglia. Neural Plast. 2017, 2017, 6237351, DOI: 10.1155/2017/6237351[Crossref], [PubMed], [CAS], Google Scholar221https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1czmtF2ksA%253D%253D&md5=643cb3e29100fa3f60d9c121a8c25530Proteomic Analysis of HDAC3 Selective Inhibitor in the Regulation of Inflammatory Response of Primary MicrogliaXia Mingxu; Zhao Qiuchen; Zhang He; Chen Yanting; Xu Yun; Zhang Meijuan; Yuan ZengqiangNeural plasticity (2017), 2017 (), 6237351 ISSN:.HDAC3 has been shown to regulate inflammation. However, the role of HDAC3 in primary microglia is largely unknown. RGFP966 is a newly discovered selective HDAC3 inhibitor. In this study, we used protein mass spectrometry to analyze protein alterations in LPS-treated primary microglia with the application of RGFP966. Generally, about 2000 proteins were studied. 168 of 444 (37.8%) LPS-induced proteins were significantly reduced with the treatment of RGFP966, which mainly concentrated on Toll-like receptor signaling pathway. In this regard, we selected Toll-like receptor 2 (TLR2), TLR3, TLR6, MAPK p38, CD36, and spleen tyrosine kinase (SYK) for further validation and found that they were all significantly upregulated after LPS stimulation and downregulated in the presence of RGFP966. Additionally, RGFP966 inhibited supernatant tumor necrosis factor (TNF)-α and Interleukin 6 (IL-6) concentrations. Activation of STAT3 and STAT5 was partially blocked by RGFP966 at 2 h after LPS-stimulation. The fluorescence intensity of CD16/32 was significantly decreased in LPS + RGFP966-treated group. In conclusion, our data provided a hint that RGFP966 may be a potential therapeutic medication combating microglia activation and inflammatory response in central nervous system, which was probably related to its repressive impacts on TLR signaling pathways and STAT3/STAT5 pathways.
- 222Jia, H.; Wang, Y.; Morris, C. D.; Jacques, V.; Gottesfeld, J. M.; Rusche, J. R.; Thomas, E. A. The effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington’s disease mice. PLoS One 2016, 11, e0152498 DOI: 10.1371/journal.pone.0152498[Crossref], [PubMed], [CAS], Google Scholar222https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhtFaltbbF&md5=9e31b637a747319539e674c6c5c8adccThe effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington's disease miceJia, Haiqun; Wang, Ying; Morris, Charles D.; Jacques, Vincent; Gottesfeld, Joel M.; Rusche, James R.; Thomas, Elizabeth A.PLoS One (2016), 11 (3), e0152498/1-e0152498/14CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)An important epigenetic modification in Huntington's disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal vol. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quant. PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif), a hormone immune modulator assocd. with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its assocd. downstream effects.
- 223Suelves, N.; Kirkham-McCarthy, L.; Lahue, R. S.; Ginés, S. A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington’s disease mice. Sci. Rep. 2017, 7, 6082, DOI: 10.1038/s41598-017-05125-2[Crossref], [PubMed], [CAS], Google Scholar223https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1cjpslCmsQ%253D%253D&md5=0c384551190fd157825f8a29f675a79fA selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease miceSuelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Suelves Nuria; Gines Silvia; Kirkham-McCarthy Lucy; Lahue Robert S; Lahue Robert SScientific reports (2017), 7 (1), 6082 ISSN:.Huntington's disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating Hdh(Q111) knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.
- 224Rumbaugh, G.; Sillivan, S. E.; Ozkan, E. D.; Rojas, C. S.; Hubbs, C. R.; Aceti, M.; Kilgore, M.; Kudugunti, S.; Puthanveettil, S. V.; Sweatt, J. D.; Rusche, J.; Miller, C. A. Pharmacological selectivity within class i histone deacetylases predicts effects on synaptic function and memory rescue. Neuropsychopharmacology 2015, 40, 2307– 2316, DOI: 10.1038/npp.2015.93[Crossref], [PubMed], [CAS], Google Scholar224https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXnsFOqurk%253D&md5=8b92747830ff7b8b31ce46fb00aa6e5aPharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory RescueRumbaugh, Gavin; Sillivan, Stephanie E.; Ozkan, Emin D.; Rojas, Camilo S.; Hubbs, Christopher R.; Aceti, Massimiliano; Kilgore, Mark; Kudugunti, Shashi; Puthanveettil, Sathyanarayanan V.; Sweatt, J. David; Rusche, James; Miller, Courtney A.Neuropsychopharmacology (2015), 40 (10), 2307-2316CODEN: NEROEW; ISSN:0893-133X. (Nature Publishing Group)Histone deacetylases (HDACs) are promising therapeutic targets for neurol. and psychiatric disorders that impact cognitive ability, but the relationship between various HDAC isoforms and cognitive improvement is poorly understood, particularly in mouse models of memory impairment. A goal shared by many is to develop HDAC inhibitors with increased isoform selectivity in order to reduce unwanted side effects, while retaining procognitive effects. However, studies addressing this tack at the mol., cellular and behavioral level are limited. Therefore, we interrogated the biol. effects of class I HDAC inhibitors with varying selectivity and assessed a subset of these compds. for their ability to regulate transcriptional activity, synaptic function and memory. The HDAC-1, -2, and -3 inhibitors, RGFP963 and RGFP968, were most effective at stimulating synaptogenesis, while the selective HDAC3 inhibitor, RGFP966, with known memory enhancing abilities, had minimal impact. Furthermore, RGFP963 increased hippocampal spine d., while HDAC3 inhibition was ineffective. Genome-wide gene expression anal. by RNA sequencing indicated that RGFP963 and RGFP966 induce largely distinct transcriptional profiles in the dorsal hippocampus of mature mice. The results of bioinformatic analyses were consistent with RGFP963 inducing a transcriptional program that enhances synaptic efficacy. Finally, RGFP963, but not RGFP966, rescued memory in a mouse model of Alzheimer's Disease. Together, these studies suggest that the specific memory promoting properties of class I HDAC inhibitors may depend on isoform selectivity and that certain pathol. brain states may be more receptive to HDAC inhibitors that improve network function by enhancing synapse efficacy.
- 225Rogge, G. A.; Singh, H.; Dang, R.; Wood, M. A. HDAC3 is a negative regulator of cocaine-context-associated memory formation. J. Neurosci. 2013, 33, 6623– 6632, DOI: 10.1523/JNEUROSCI.4472-12.2013[Crossref], [PubMed], [CAS], Google Scholar225https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtl2jtrfE&md5=69819c3e67ab3fe110c11fc7bbecde9fHDAC3 is a negative regulator of cocaine-context-associated memory formationRogge, George A.; Singh, Harsimran; Dang, Richard; Wood, Marcelo A.Journal of Neuroscience (2013), 33 (15), 6623-6632CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Cocaine-induced neuroplasticity mediated by histone acetylating and deacetylating enzymes may contribute to addiction-like behaviors. For example, overexpression of histone deacetylases (HDACs) 4 or 5 in the nucleus accumbens suppresses cocaine-induced conditioned place preference (CPP) acquisition in mice. HDAC4 and HDAC5 are known to interact with HDAC3, but the role of HDAC3 in cocaine-induced behaviors has never been examd. In this study, we address the hypothesis that HDAC3 is a neg. regulator of cocaine-context-assocd. memory formation in mice. We examd. the role of HDAC3 during the conditioning phase of CPP, when the mouse has the opportunity to form an associative memory between the cocaine-paired context and the subjective effects of cocaine. To address this hypothesis, Hdac3flox/flox and Hdac3+/+ mice (generated from a C57BL/6 background) were infused into the nucleus accumbens with adeno-assocd. virus expressing Cre recombinase to create focal, homozygous Hdac3 deletions. Hdac3flox/flox mice exhibit significantly enhanced CPP acquisition, which is correlated with increased gene expression during the consolidation phase of acquisition. Increased gene expression of c-Fos and Nr4a2 is correlated with decreased HDAC3 occupancy and increased histone H4 lysine 8 acetylation at their promoters. The results from this study demonstrate that HDAC3 neg. regulates cocaine-induced CPP acquisition.
- 226Malvaez, M.; McQuown, S. C.; Rogge, G. A.; Astarabadi, M.; Jacques, V.; Carreiro, S.; Rusche, J. R.; Wood, M. A. HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 2647– 2652, DOI: 10.1073/pnas.1213364110[Crossref], [PubMed], [CAS], Google Scholar226https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXjsVCnsb4%253D&md5=37fd432cbf96bd2c30b7d5ac9eefcf45HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent mannerMalvaez, Melissa; McQuown, Susan C.; Rogge, George A.; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R.; Wood, Marcelo A.Proceedings of the National Academy of Sciences of the United States of America (2013), 110 (7), 2647-2652, S2647/1-S2647/4CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to neg. effects on performance or reconsolidation. These are key distinctions with regard to any compd. being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.
- 227McQuown, S. C.; Barrett, R. M.; Matheos, D. P.; Post, R. J.; Rogge, G. A.; Alenghat, T.; Mullican, S. E.; Jones, S.; Rusche, J. R.; Lazar, M. A.; Wood, M. A. HDAC3 is a critical negative regulator of long-term memory formation. J. Neurosci. 2011, 31, 764– 774, DOI: 10.1523/JNEUROSCI.5052-10.2011[Crossref], [PubMed], [CAS], Google Scholar227https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXht1ars70%253D&md5=02f22e34e095ac5fe5e5b6217821b8ccHDAC3 is a critical negative regulator of long-term memory formationMcQuown, Susan C.; Barrett, Ruth M.; Matheos, Dina P.; Post, Rebecca J.; Rogge, George A.; Alenghat, Theresa; Mullican, Shannon E.; Jones, Steven; Rusche, James R.; Lazar, Mitchell A.; Wood, Marcelo A.Journal of Neuroscience (2011), 31 (2), 764-774CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation neg. regulates transcription. The interplay between histone acetyltranserases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examd. the role of HDAC3 in long-term memory using a combined genetic and pharmacol. approach. We used HDAC3-FLOX genetically modified mice in combination with adeno-assocd. virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochem. showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examd. expression of genes implicated in long-term memory from dorsal hippocampal punches using quant. reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3-FLOX mice compared with wild-type controls. Memory enhancements obsd. in HDAC3-FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 neg. regulates memory formation. Together, these findings demonstrate a crit. role for HDAC3 in the mol. mechanisms underlying long-term memory formation.
- 228Sanchez, S.; Lemmens, S.; Baeten, P.; Sommer, D.; Dooley, D.; Hendrix, S.; Fabregas, M. G. HDAC3 inhibition promotes alternative activation of macrophages but does not affect functional recovery after spinal cord injury. Exp. Neurobiol. 2018, 27, 437– 452, DOI: 10.5607/en.2018.27.5.437[Crossref], [PubMed], [CAS], Google Scholar228https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3crgtFeisQ%253D%253D&md5=e8fe8c84a3f84a0bfc4c16ea7cfb5909HDAC3 Inhibition Promotes Alternative Activation of Macrophages but Does Not Affect Functional Recovery after Spinal Cord InjurySanchez Selien; Lemmens Stefanie; Baeten Paulien; Sommer Daniela; Hendrix Sven; Gou Fabregas Myriam; Dooley DearbhaileExperimental neurobiology (2018), 27 (5), 437-452 ISSN:1226-2560.After spinal cord injury (SCI), monocyte derived macrophages play a detrimental role. Histone deacetylases (HDACs) are central epigenetic regulators of macrophage-polarization. We hypothesized that HDAC3 inhibition suppresses the pro-inflammatory macrophage phenotype (M1), promotes the anti-inflammatory phenotype (M2) and improves functional recovery after SCI. Therefore, two inhibitors of HDAC3 were selected, namely scriptaid and RGFP966. The impact on macrophage polarization was studied by investigating the effect on gene and protein expression of selected M1 and M2 markers. We show that scriptaid differentially influences M1 and M2 markers. It increases CD86 and iNOS gene expression and decreases GPR18, CD38, FPR2 and Arg-1 gene expression as well as the production of IL-6 and NO. RGFP966 primarily increased the expression of the M2 markers Arg-1 and Ym1 and reduced the production of IL-6 (M1). RGFP966 and scriptaid reduced the formation of foamy macrophages. Finally, to investigate the impact of HDAC3 inhibition on functional recovery after SCI, we studied the effects of RGFP966 and scriptaid in an in vivo T-cut hemisection SCI model. Histological analyses were performed on spinal cord sections to determine lesion size and astrogliosis, demyelinated area and selected infiltrating immune cells. RGFP966 and scriptaid did not affect functional recovery or histopathological outcome after SCI. In conclusion, these results indicate that specific HDAC3 inhibition with RGFP966 promotes alternative activation of macrophages and reduces the formation of foamy macrophages, but does not lead to a better functional recovery after SCI.
- 229Yang, X.; Wu, Q.; Zhang, L.; Feng, L. Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in rats. Front. Mol. Neurosci. 2016, 9, 131, DOI: 10.3389/fnmol.2016.00131[Crossref], [PubMed], [CAS], Google Scholar229https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhtV2itrbF&md5=91895280c5b732f55f01cf5d7e283956Inhibition of histone deacetylase 3 (HDAC3) mediates ischemic preconditioning and protects cortical neurons against ischemia in ratsYang, Xiaoyu; Wu, Qimei; Zhang, Lei; Feng, LinyinFrontiers in Molecular Neuroscience (2016), 9 (), 131/1-131/14CODEN: FMNRAJ; ISSN:1662-5099. (Frontiers Media S.A.)Brain ischemic preconditioning (PC) provides vital insights into the endogenous protection against stroke. Genomic and epigenetic responses to PC condition the brain into a state of ischemic tolerance. Notably, PC induces the elevation of histone acetylation, consistent with evidence that histone deacetylase (HDAC) inhibitors protect the brain from ischemic injury. However, less is known about the specific roles of HDACs in this process. HDAC3 has been implicated in several neurodegenerative conditions. Deletion of HDAC3 confers protection against neurotoxicity and neuronal injury. Here, we hypothesized that inhibition of HDAC3 may contribute to the neuronal survival elicited by PC. To address this notion, PC and transient middle cerebral artery occlusion (MCAO) were conducted in Sprague-Dawley rats. Addnl., primary cultured cortical neurons were used to identify the modulators and effectors of HDAC3 involved in PC. We found that nuclear localization of HDAC3 was significantly reduced following PC in vivo and in vitro. Treatment with the HDAC3-specific inhibitor, RGFP966, mimicked the neuroprotective effects of PC 24 h and 7 days after MCAO, causing a reduced infarct vol. and less Fluoro-Jade C staining. Improved functional outcomes were obsd. in the neurol. score and rotarod test. We further showed that attenuated recruitment of HDAC3 to promoter regions following PC potentiates transcriptional initiation of genes including Hspa1a, Bcl2l1, and Prdx2, which may underlie the mechanism of protection. In addn., PC-activated calpains were implicated in the cleavage of HDAC3. Pretreatment with calpeptin blockaded the attenuated nuclear distribution of HDAC3 and the protective effect of PC in vivo. Collectively, these results demonstrate that the inhibition of HDAC3 preconditions the brain against ischemic insults, indicating a new approach to evoke endogenous protection against stroke.
- 230Duncan, C. E.; An, M. C.; Papanikolaou, T.; Rugani, C.; Vitelli, C.; Ellerby, L. M. Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model. Mol. Neurodegener. 2013, 8, 42, DOI: 10.1186/1750-1326-8-42[Crossref], [PubMed], [CAS], Google Scholar230https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXlsVyhs7c%253D&md5=6bc7fc14246895d5b04488775df303e7Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse modelDuncan, Carlotta E.; An, Mahru C.; Papanikolaou, Theodora; Rugani, Caitlin; Vitelli, Cathy; Ellerby, Lisa M.Molecular Neurodegeneration (2013), 8 (), 42/1-42/14, 14 pp.CODEN: MNOEAZ; ISSN:1750-1326. (BioMed Central Ltd.)Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity assocd. with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 phys. interacts with ataxin-7. The phys. interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors.
- 231Krishna, K.; Behnisch, T.; Sajikumar, S. Inhibition of histone deacetylase 3 restores amyloid-β oligomer-induced plasticity deficit in hippocampal CA1 pyramidal neurons. J. Alzheimer's Dis. 2016, 51, 783– 791, DOI: 10.3233/JAD-150838[Crossref], [PubMed], [CAS], Google Scholar231https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xlt1SksLY%253D&md5=55aa2393e083fd5654a60fd878527a58Inhibition of Histone Deacetylase 3 Restores Amyloid-β Oligomer-Induced Plasticity Deficit in Hippocampal CA1 Pyramidal NeuronsKrishna, Kumar; Behnisch, Thomas; Sajikumar, Sreedharan; Arancio, OttavioJournal of Alzheimer's Disease (2016), 51 (3), 783-791CODEN: JADIF9; ISSN:1387-2877. (IOS Press)Neurodegenerative diseases such as Alzheimer's disease (AD) are assocd. with alterations in epigenetic factors leading to cognitive decline. Histone deacetylase 3 (HDAC3) is a known crit. epigenetic neg. regulator of learning and memory. In this study, attenuation of long-term potentiation by amyloid-β oligomer, and its reversal by specific HDAC3 inhibitor RGFP966, was performed in rat CA1 pyramidal neurons using whole cell voltage-clamp and field recording techniques. Our findings provide the first evidence that amyloid-β oligomer-induced synaptic plasticity impairment can be prevented by inhibition of HDAC3 enzyme both at the single neuron as well as in a population of neurons, thus identifying HDAC3 as a potential target for ameliorating AD related plasticity impairments.
- 232Gillespie, J.; Savic, S.; Wong, C.; Hempshall, A.; Inman, M.; Emery, P.; Grigg, R.; McDermott, M. F. Histone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Rheum. 2012, 64, 418– 422, DOI: 10.1002/art.33382[Crossref], [PubMed], [CAS], Google Scholar232https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xht1yru7c%253D&md5=6ac55ccb9ffcd2c1d4e2d93dabcdc71eHistone deacetylases are dysregulated in rheumatoid arthritis and a novel histone deacetylase 3-selective inhibitor reduces interleukin-6 production by peripheral blood mononuclear cells from rheumatoid arthritis patientsGillespie, Justin; Savic, Sinisa; Wong, Chi; Hempshall, Aiden; Inman, Martyn; Emery, Paul; Grigg, Ronald; McDermott, Michael F.Arthritis & Rheumatism (2012), 64 (2), 418-422CODEN: ARHEAW; ISSN:0004-3591. (John Wiley & Sons, Inc.)To characterize the role of histone deacetylase (HDAC) activity in rheumatoid arthritis (RA) and to evaluate the effects of MI192, a novel HDAC-3-selective inhibitor, compared with the established nonselective HDAC inhibitor trichostatin A (TSA), on proinflammatory cytokine prodn. Activity of HDAC and histone acetyltransferase was measured in peripheral blood mononuclear cells (PBMCs) from RA patients by spectrophotometric assay, prior to and after 12 wk of etanercept therapy. The effects of HDAC inhibitor treatment on cytokine prodn. in both RA and healthy PBMCs were assessed by ELISA. RA PBMCs exhibited significantly increased HDAC activity (P = 0.007) compared to PBMCs from healthy individuals, and the increase was unaltered after 12 wk of etanercept therapy. TSA was a potent inhibitor of tumor necrosis factor (TNF) and interleukin-6 (IL-6) prodn. in both RA and healthy PBMCs and of interferon-γ (IFNγ) prodn. in healthy PBMCs; IFNγ was not produced by RA PBMCs. MI192 inhibited TNF prodn. at high concns. and dose-dependently inhibited IL-6 in RA PBMCs but not healthy PBMCs, across a dose range of 10 μM-5 nM. HDAC activity is dysregulated in RA PBMCs and is a potential target for therapeutic intervention, as it is not affected by conventional anti-TNF treatment with etanercept. Both the selective and the nonselective HDAC inhibitors (MI192 and TSA, resp.) were found to regulate cytokine prodn. from PBMCs, but their effects were cell type and compd. specific. HDAC inhibitors have potential in the treatment of RA, and HDAC-selective inhibition may improve the therapeutic margin of safety; however, further clin. characterization and evaluation for adverse effects is needed.
- 233Chen, X.; Barozzi, I.; Termanini, A.; Prosperini, E.; Recchiuti, A.; Dalli, J.; Mietton, F.; Matteoli, G.; Hiebert, S.; Natoli, G. Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, E2865– E2874, DOI: 10.1073/pnas.1121131109[Crossref], [PubMed], [CAS], Google Scholar233https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhs1Wmsb%252FO&md5=15742ff99ed4eee55d890d640daee450Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophagesChen, Xuefen; Barozzi, Iros; Termanini, Alberto; Prosperini, Elena; Recchiuti, Antonio; Dalli, Jesmond; Mietton, Flore; Matteoli, Gianluca; Hiebert, Scott; Natoli, GioacchinoProceedings of the National Academy of Sciences of the United States of America (2012), 109 (42), E2865-E2874, SE2865/1-SE2865/89CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)Histone deacetylases (HDACs) regulate inflammatory gene expression, as indicated by the potent antiinflammatory activity of pan-HDAC inhibitors. However, the specific contribution of each of the 11 HDAC proteins to the inflammatory gene expression program is unknown. Using an integrated genomic approach, we found that Hdac3-deficient macrophages were unable to activate almost half of the inflammatory gene expression program when stimulated with LPS. A large part of the activation defect was attributable to loss of basal and LPS-inducible expression of IFN-β, which maintains Stat1 protein levels in unstimulated cells and acts in an autocrine/paracrine manner after stimulation to promote a secondary wave of Stat1-dependent gene expression. Loss of Hdac3-mediated repression of nuclear receptors led to hyperacetylation of thousands of genomic sites and assocd. gene derepression. The up-regulation of the constitutively expressed prostaglandin endoperoxide synthase, Ptgs1 (Cox-1), a nuclear receptor target, had a causative role in the phenotype because its chem. inhibition reverted, albeit partially, the Ifn-β activation defect. These data indicate a central role for Hdac3 in inflammation and may have relevance for the use of selective Hdac inhibitors as antiinflammatory agents.
- 234Zhang, H.; Ji, L.; Yang, Y.; Wei, Y.; Zhang, X.; Gang, Y.; Lu, J.; Bai, L. The Therapeutic effects of treadmill exercise on osteoarthritis in rats by inhibiting the HDAC3/NF-KappaB pathway in vivo and in vitro. Front. Physiol. 2019, 10, 1060, DOI: 10.3389/fphys.2019.01060[Crossref], [PubMed], [CAS], Google Scholar234https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3MrkvVKksQ%253D%253D&md5=d761f4b0ceb59380384ae4595381fa3eThe Therapeutic Effects of Treadmill Exercise on Osteoarthritis in Rats by Inhibiting the HDAC3/NF-KappaB Pathway in vivo and in vitroZhang He; Yang Yue; Wei Yingliang; Lu Jinghan; Bai Lunhao; Ji Lu; Zhang Xiaoning; Gang YiFrontiers in physiology (2019), 10 (), 1060 ISSN:1664-042X.Osteoarthritis (OA) is a disease characterized by non-bacterial inflammation. Histone deacetylase 3 (HDAC3) is a crucial positive regulator in the inflammation that leads to the development of non-OA inflammatory disease. However, the precise involvement of HDAC3 in OA is still unknown, and the underlying mechanism of exercise therapy in OA requires more research. We investigated the involvement of HDAC3 in exercise therapy-treated OA. Expression levels of HDAC3, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), matrix metalloproteinase-13 (MMP-13), HDAC3 and nuclear factor-kappaB (NF-kappaB) were measured by western blotting, reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Cartilage damage and OA evaluation were measured by hematoxylin and eosin staining and Toluidine blue O staining according to the Mankin score and OARSI score, respectively. We found that moderate-intensity treadmill exercise could relieve OA. Meanwhile, the expression of HDAC3, MMP-13, ADAMTS-5 and NF-kappaB decreased, and collagen II increased in the OA + moderate-intensity treadmill exercise group (OAM) compared with the OA group (OAG) or OA + high- or low-intensity treadmill exercise groups (OAH or OAL). Furthermore, we found the selective HDAC3 inhibitor RGFP966 could also alleviate inflammation in OA rat model through inhibition of nuclear translocation of NF-kappaB. To further explore the relationship between HDAC3 and NF-kappaB, we investigated the change of NF-kappaB relocation in IL-1β-treated chondrocytes under the stimulation of RGFP966. We found that RGFP966 could inhibit the expression of inflammatory markers of OA via regulation of HDAC3/NF-kappaB pathway. These investigations revealed that RGFP966 is therefore a promising new drug for treating OA.
- 235Hoeksema, M. A.; Gijbels, M. J.; Van den Bossche, J.; Velden, S.; Sijm, A.; Neele, A. E.; Seijkens, T.; Stöger, J. L.; Meiler, S.; Boshuizen, M. C.; Dallinga-Thie, G. M.; Levels, J. H.; Boon, L.; Mullican, S. E.; Spann, N. J.; Cleutjens, J. P.; Glass, C. K.; Lazar, M. A.; Vries, C. J.; Biessen, E. A.; Daemen, M. J.; Lutgens, E.; Winther, M. P. Targeting macrophage histone deacetylase 3 stabilizes atherosclerotic lesions. EMBO Mol. Med. 2014, 6, 1124– 1132, DOI: 10.15252/emmm.201404170[Crossref], [PubMed], [CAS], Google Scholar235https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsVCmur%252FF&md5=6ada26dd828f8bde3c756c0ba6632e32Targeting macrophage Histone deacetylase 3 stabilizes atherosclerotic lesionsHoeksema, Marten A.; Gijbels, Marion JJ; Van den Bossche, Jan; van der Velden, Saskia; Sijm, Ayestha; Neele, Annette E.; Seijkens, Tom; Stoeger, J. Lauran; Meiler, Svenja; Boshuizen, Marieke CS; Dallinga-Thie, Geesje M.; Levels, Johannes HM; Boon, Louis; Mullican, Shannon E.; Spann, Nathanael J.; Cleutjens, Jack P.; Glass, Chris K.; Lazar, Mitchell A.; de Vries, Carlie JM; Biessen, Erik AL; Daemen, Mat JAP; Lutgens, Esther; de Winther, Menno PJEMBO Molecular Medicine (2014), 6 (9), 1124-1132CODEN: EMMMAM; ISSN:1757-4684. (Wiley-Blackwell)Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. Targeting the functional repertoire of macrophages may hold novel approaches for future atherosclerosis management. Here, we describe a previously unrecognized role of the epigenomic enzyme Histone deacetylase 3 (Hdac3) in regulating the atherosclerotic phenotype of macrophages. Using conditional knockout mice, we found that myeloid Hdac3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling. The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon Hdac3 deletion, driving smooth muscle cells to increased collagen prodn. Moreover, in humans, HDAC3 was the sole Hdac upregulated in ruptured atherosclerotic lesions, Hdac3 assocd. with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Collectively, we show that targeting the macrophage epigenome can improve atherosclerosis outcome and we identify Hdac3 as a potential novel therapeutic target in cardiovascular disease.
- 236Lewandowski, S. L.; Janardhan, H. P.; Trivedi, C. M. Histone Deacetylase 3 coordinates deacetylase-independent epigenetic silencing of transforming growth factor-β1 (TGF-β1) to orchestrate second heart field development. J. Biol. Chem. 2015, 290, 27067– 27089, DOI: 10.1074/jbc.M115.684753[Crossref], [PubMed], [CAS], Google Scholar236https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhslyrtrbP&md5=77e241bf9787f93b2cae75c62957b6c7Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field DevelopmentLewandowski, Sara L.; Janardhan, Harish P.; Trivedi, Chinmay M.Journal of Biological Chemistry (2015), 290 (45), 27067-27089CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is assocd. with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacol. inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.
- 237Cavasin, M. A.; Demos-Davies, K.; Horn, T. R.; Walker, L. A.; Lemon, D. D.; Birdsey, N.; Weiser-Evans, M. C.; Harral, J.; Irwin, D. C.; Anwar, A.; Yeager, M. E.; Li, M.; Watson, P. A.; Nemenoff, R. A.; Buttrick, P. M.; Stenmark, K. R.; McKinsey, T. A. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ. Res. 2012, 110, 739– 748, DOI: 10.1161/CIRCRESAHA.111.258426[Crossref], [PubMed], [CAS], Google Scholar237https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XjtV2nu7g%253D&md5=f419a07195352059951c5bf76cbb30fdSelective Class I Histone Deacetylase Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Antiproliferative MechanismCavasin, Maria A.; Demos-Davies, Kim; Horn, Todd R.; Walker, Lori A.; Lemon, Douglas D.; Birdsey, Nicholas; Weiser-Evans, Mary C. M.; Harral, Julie; Irwin, David C.; Anwar, Adil; Yeager, Michael E.; Li, Min; Watson, Peter A.; Nemenoff, Raphael A.; Buttrick, Peter M.; Stenmark, Kurt R.; McKinsey, Timothy A.Circulation Research (2012), 110 (5), 739-748CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension with assocd. right ventricular cardiac remodeling are poorly understood. Objective: This study was performed to assess the utility of selective small-mol. inhibitors of class I HDACs in a preclin. model of pulmonary hypertension. Methods and results: Rats were exposed to hypobaric hypoxia for 3 wk in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compd. reduced pulmonary arterial pressure more dramatically than tadalafil, a std.-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a pos. impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was assocd. with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathol. gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. Conclusions: By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for pulmonary hypertension that will complement vasodilator stds. of care.
- 238Kee, H. J.; Kim, G. R.; Lin, M. Q.; Choi, S. Y.; Ryu, Y.; Jin, L.; Piao, Z. H.; Jeong, M. H. Expression of class I and class II a/b histone deacetylase is dysregulated in hypertensive animal models. Korean Circ. J. 2017, 47, 392– 400, DOI: 10.4070/kcj.2016.0266[Crossref], [PubMed], [CAS], Google Scholar238https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXht1eqsL%252FJ&md5=b5841463ecc31ecca07bd32804091e12Expression of class I and class II a/b histone deacetylase is dysregulated in hypertensive animal modelsKee, Hae Jin; Kim, Gwi Ran; Lin, Ming Ouan; Choi, Sin Young; Ryu, Yuhee; Jin, Li; Piao, Zhe Hao; Jeong, Myung HoKorean Circulation Journal (2017), 47 (3), 392-400CODEN: KCJOA9; ISSN:1738-5520. (Korean Society of Cardiology)Background and Objectives: Dysregulation of histone deacetylase expression and enzymic activity is assocd. with a no. of diseases. It has been reported that protein levels of histone deacetylase (HDAC)1 and HDAC5 increase during human pulmonary hypertension, and that the enzymic activity of HDAC6 is induced in a chronic hypertensive animal model. This study investigated the protein expression profiles of class I and II a/b HDACs in three systemic hypertension models. Materials and Methods: We used three different hypertensive animal models: (i) Wistar-Kyoto rats (n=8) and spontaneously hypertensive rats (SHR; n=8), (ii) mice infused with saline or angiotensin II to irduce hypertension, via osmotic mini-pump for 2 wk, and (iii) mice that were allowed to drink L-NG-nitro-L-arginine Me ester (L-NAME) to induce hypertension. Results: SHR showed high systolic, diastolic, and mean blood pressures. Similar increases in systolic blood pressure were obsd. in angiotensin II or L-NAME-induced hypertensive mice. In SHR, class IIa HDAC (HDAC4, 5, and 7) and class IIb HDAC (HDAC6 and 10) protein expression were significantly increased. In addn., a HDAC3 protein expression was induced in SHR. However, in L-NAME mice, class IIa HDAC protein levels (HDAC4, 5, 7, and 9) were significantly reduced. HDAC8 protein levels were significantly reduced both in angiotensin II mice and in SHR. Conclusion: These results indicate that dysregulation of class I and class II HDAC protein is closely assocd. with chronic hypertension.
- 239Sharifi-Sanjani, M.; Shoushtari, A. H.; Quiroz, M.; Baust, J.; Sestito, S. F.; Mosher, M.; Ross, M.; McTiernan, C. F.; St. Croix, C. M.; Bilonick, R. A.; Champion, H. C.; Isenberg, J. S. Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3. J. Am. Heart Assoc. 2014, 3, e000670 DOI: 10.1161/JAHA.113.000670[Crossref], [PubMed], [CAS], Google Scholar239https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhslWgu73K&md5=27b9795123d46ac46c07be40348f01b0Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3Sharifi-Sanjani, Maryam; Shoushtari, Ali Hakim; Quiroz, Marisol; Baust, Jeffrey; Sestito, Samuel F.; Mosher, Mackenzie; Ross, Mark; McTiernan, Charles F.; St. Croix, Claudette M.; Bilonick, Richard A.; Champion, Hunter C.; Isenberg, Jeffrey S.Journal of the American Heart Association (2014), 3 (3), e000670/1-e000670/22, 22 pp.CODEN: JAHABZ; ISSN:2047-9980. (Wiley-Blackwell)Background: Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger nos. of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high-affinity secreted ligand, thrombospondin 1 (TSP 1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed. Methods and Results: In exptl. LVHF TSP 1-CD47 signaling is increased concurrent with up-regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)-driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1-derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca2+/calmodulin protein kinase II (CaMKII)-dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacol. inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals. Conclusions: These data identify a proximate role for the TSP 1-CD47 axis in promoting LVHF by CaKMII-mediated up-regulation of HDAC3 and suggest novel therapeutic opportunities.
- 240Lyu, X.; Hu, M.; Peng, J.; Zhang, X.; Sanders, Y. Y. HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis. Ther. Adv. Chronic Dis. 2019, 10, 2040622319862697, DOI: 10.1177/2040622319862697
- 241Ryu, Y.; Kee, H. J.; Sun, S.; Seok, Y. M.; Choi, S. Y.; Kim, G. R.; Kee, S. J.; Pflieger, M.; Kurz, T.; Kim, H. S.; Jeong, M. H. Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertension. PLoS One 2019, 14, e0213186 DOI: 10.1371/journal.pone.0213186[Crossref], [PubMed], [CAS], Google Scholar241https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXmt1SmtLo%253D&md5=baf89fbc5960f31d05eb854fab2db203Class I histone deacetylase inhibitor MS-275 attenuates vasoconstriction and inflammation in angiotensin II-induced hypertensionRyu, Yuhee; Kee, Hae Jin; Sun, Simei; Seok, Young Mi; Choi, Sin Young; Kim, Gwi Ran; Kee, Seung-Jung; Pflieger, Marc; Kurz, Thomas; Kim, Hyung-Seok; Jeong, Myung HoPLoS One (2019), 14 (3), e0213186CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Non-selective histone deacetylase (HDAC) inhibitors are known to improve hypertension. Here, we investigated the therapeutic effect and regulatory mechanism of the class I HDAC selective inhibitors, MS-275 and RGFP966, in angiotensin (Ang) II-induced hypertensive mice. MS-275 and RGFP966 treatment reduced systolic blood pressure and thickness of the aorta wall in Ang II-induced hypertensive mice. MS-275 decreased the components of the renin angiotensin system and increased vascular relaxation of rat aortic rings via the nitric oxide (NO) pathway. NO levels reduced by Ang II were restored by MS-275 treatment in vascular smooth muscle cells (VSMCs). However, MS-275 dose (3 mg·kg-1·day-1) was not enough to induce NO prodn. in vivo. In addn., MS-275 did not prevent endothelial nitric oxide synthase (eNOS) uncoupling in the aorta of Ang II-induced mice. Treatment with MS-275 failed to inhibit Ang II-induced expression of NADPH oxidase (Nox)1, Nox2, and p47phox. MS-275 treatment reduced proinflammatory cytokines such as tumor necrosis factor (TNF)-a, IL-1β, and MCP-1, as well as adhesion mols. Histol. anal. showed that Ang II-induced macrophage infiltration was reduced by MS-275 and RGFP966 administration. Our results indicate that class I HDAC selective inhibitors may be good therapeutic agents for the treatment of hypertension through the regulation of vascular remodeling and vasoconstriction, as well as inflammation.
- 242Zhao, B.; Yuan, Q.; Hou, J. B.; Xia, Z. Y.; Zhan, L. Y.; Li, M.; Jiang, M.; Gao, W. W.; Liu, L. Inhibition of HDAC3 ameliorates cerebral ischemia reperfusion injury in diabetic mice in vivo and in vitro. J. Diabetes Res. 2019, 2019, 8520856, DOI: 10.1155/2019/8520856[Crossref], [PubMed], [CAS], Google Scholar242https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BB3cbns1KjsA%253D%253D&md5=c182705768ad3a5bedeb4cce0238cbc8Inhibition of HDAC3 Ameliorates Cerebral Ischemia Reperfusion Injury in Diabetic Mice In Vivo and In VitroZhao Bo; Yuan Quan; Hou Jia-Bao; Xia Zhong-Yuan; Zhan Li-Ying; Li Mei; Jiang Meng; Liu Lian; Gao Wen-WeiJournal of diabetes research (2019), 2019 (), 8520856 ISSN:.Background: A substantial increase in histone deacetylase 3 (HDAC3) expression is implicated in the pathological process of diabetes and stroke. However, it is unclear whether HDAC3 plays an important role in diabetes complicated with stroke. We aimed to explore the role and the potential mechanisms of HDAC3 in cerebral ischemia/reperfusion (I/R) injury in diabetic state. Methods: Diabetic mice were subjected to 1 h ischemia, followed by 24 h reperfusion. PC12 cells were exposed to high glucose for 24 h, followed by 3 h of hypoxia and 6 h of reoxygenation (H/R). Diabetic mice received RGFP966 (the specific HDAC3 inhibitor) or vehicle 30 minutes before the middle cerebral artery occlusion (MCAO), and high glucose-incubated PC12 cells were pretreated with RGFP966 or vehicle 6 h before H/R. Results: HDAC3 inhibition reduced the cerebral infarct volume, ameliorated pathological changes, improved the cell viability and cytotoxicity, alleviated apoptosis, attenuated oxidative stress, and enhanced autophagy in cerebral I/R injury model in diabetic state in vivo and in vitro. Furthermore, we found that the expression of HDAC3 was remarkably amplified, and the Bmal1 expression was notably decreased in diabetic mice with cerebral I/R, whereas this phenomenon was obviously reversed by RGFP966 pretreatment. Conclusions: These results suggested that the HDAC3 was involved in the pathological process of the complex disease of diabetic stroke. Suppression of HDAC3 exerted protective effects against cerebral I/R injury in diabetic state in vivo and in vitro via the modulation of oxidative stress, apoptosis, and autophagy, which might be mediated by the upregulation of Bmal1.
- 243Zhang, J.; Xu, Z.; Gu, J. L.; Jiang, S. Z.; Liu, Q.; Zheng, Y.; Freedman, J. H.; Sun, J.; Cai, L. HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetesinduced liver damage and FGF21 synthesis and secretion leading to aortic protection. Am. J. Physiol-Endoc M 2018, 315, E150– E162, DOI: 10.1152/ajpendo.00465.2017
- 244Villagra, A.; Ulloa, N.; Zhang, X.; Yuan, Z.; Sotomayor, E.; Seto, E. Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression. J. Biol. Chem. 2007, 282, 35457– 35470, DOI: 10.1074/jbc.M701719200[Crossref], [PubMed], [CAS], Google Scholar244https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXhtlKrsLfE&md5=669b2e6162605b83c5a53be2a2525356Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene ExpressionVillagra, Alejandro; Ulloa, Natalia; Zhang, Xiaohong; Yuan, Zhigang; Sotomayor, Eduardo; Seto, EdwardJournal of Biological Chemistry (2007), 282 (49), 35457-35470CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), E.C. 5.4.99.7). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochem. functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that histone deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concns. compared with parental cells. Extensive promoter analyses coupled with chromatin immunopptn. assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.
- 245Joshi, A. D.; Barabutis, N.; Birmpas, C.; Dimitropoulou, C.; Thangjam, G.; Cherian-Shaw, M.; Dennison, J.; Catravas, J. D. Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. Am. J. Physiol. Lung Cell Mol. Physiol. 2015, 309, L1410– L1419, DOI: 10.1152/ajplung.00180.2015
- 246Zhang, X.; Ozawa, Y.; Lee, H.; Wen, Y. D.; Tan, T. H.; Wadzinski, B. E.; Seto, E. Histone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4. Genes Dev. 2005, 19, 827– 839, DOI: 10.1101/gad.1286005[Crossref], [PubMed], [CAS], Google Scholar246https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2MXjt1Ojtb4%253D&md5=214fae9f8751105f1df62e448f22e63dHistone deacetylase 3 (HDAC3) activity is regulated by interaction with protein serine/threonine phosphatase 4Zhang, Xiaohong; Ozawa, Yukiyasu; Lee, Heehyoung; Wen, Yu-Der; Tan, Tse-Hua; Wadzinski, Brian E.; Seto, EdwardGenes & Development (2005), 19 (7), 827-839CODEN: GEDEEP; ISSN:0890-9369. (Cold Spring Harbor Laboratory Press)Histone deacetylase 3 (HDAC3) is one of four members of the human class I HDACs that regulates gene expression by deacetylation of histones and nonhistone proteins. Early studies have suggested that HDAC3 activity is regulated by assocn. with the corepressors N-CoR and SMRT. Here the authors demonstrate that, in addn. to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity. Interestingly, unlike other class I HDACs, HDAC3 uniquely copurifies with the catalytic and regulatory subunits of the protein serine/threonine phosphatase 4 complex (PP4c/PP4R1). Furthermore, HDAC3 complexes displayed protein phosphatase activity and a series of subsequent mutational analyses revealed that the N terminus of HDAC3 (residues 1-122) was both necessary and sufficient for HDAC3-PP4c interactions. Significantly, both overexpression and siRNA knock-down approaches, and anal. of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4c. These findings therefore further highlight the importance of protein-protein interactions and extend the significance of dephosphorylation in the regulation of HDAC activity, as well as present a novel alternative pathway by which HDAC3 activity is regulated.
- 247Gu, L. Z.; Sun, H.; Chen, J. H. Histone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathways. Biomed. Pharmacother. 2017, 85, 756– 762, DOI: 10.1016/j.biopha.2016.11.094[Crossref], [PubMed], [CAS], Google Scholar247https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XhvF2mtbvF&md5=f10d3c567f3dcc915cea3a956f3b680fHistone deacetylases 3 deletion restrains PM2.5-induced mice lung injury by regulating NF-κB and TGF-β/Smad2/3 signaling pathwaysGu, Li-Zhi; Sun, Hong; Chen, Jian-HuiBiomedicine & Pharmacotherapy (2017), 85 (), 756-762CODEN: BIPHEX; ISSN:0753-3322. (Elsevier Masson SAS)Acute lung injury (ALI) as a serious disease with high mortality has been emphasized as a threat to human health and life. Accumulating studies demonstrated that PM2.5 plays a significant role in metabolic and lung diseases. Histone deacetylases 3 (HDAC3) is an important regulator in control of gene transcription, required in up-regulation of inflammation-related signaling, and has been known as a key hotpot in treating a lot of chronic inflammatory diseases. TGF-β/Smad signaling pathway has been proven to be of significance in fibrosis development. Our results found that PM2.5 induced lung function injury in WT mice with a inflammatory responses through the activation of TGF-β/Smad signaling pathways, resulting in lung injury. Of note, HDAC3-deficient mice after PM2.5 administration further promoted TGF-β/Smad signaling pathways activation. In addn., TLR4, p-NF-κB and p-IκBα indicated that HDAC3 knockout mice have a higher inflammation-related signals expression in lung tissue than WT mice after PM2.5 administration, resulting in pro-inflammatory cytokines releasing. Moreover, in vitro expt. of lung epithelial cells challenged with PM2.5, further indicated that TGF-β/Smad2/3 was involved in fibrosis development, leading to inflammation response. Also, the activation of TLR4/NF-κB could be obsd. in PM2.5-induced lung epithelial cells, leading to inflammation infiltration. These results indicate a new therapeutic target to protect against lung injury caused by PM2.5.
- 248Jung, S. B.; Kim, C. S.; Naqvi, A.; Yamamori, T.; Mattagajasingh, I.; Hoffman, T. A.; Cole, M. P.; Kumar, A.; Dericco, J. S.; Jeon, B. H.; Irani, K. Histone deacetylase 3 antagonizes aspirin-stimulated endothelial nitric oxide production by reversing aspirin-induced lysine acetylation of endothelial nitric oxide synthase. Circ. Res. 2010, 107, 877– 887, DOI: 10.1161/CIRCRESAHA.110.222968[Crossref], [PubMed], [CAS], Google Scholar248https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXht1Gku7jJ&md5=f8b1fffcd599f622e09c3e04f6b9004aHistone Deacetylase 3 Antagonizes Aspirin-Stimulated Endothelial Nitric Oxide Production by Reversing Aspirin-Induced Lysine Acetylation of Endothelial Nitric Oxide SynthaseJung, Saet-Byel; Kim, Cuk-Seong; Naqvi, Asma; Yamamori, Tohru; Mattagajasingh, Ilwola; Hoffman, Timothy A.; Cole, Marsha P.; Kumar, Ajay; DeRicco, Jeremy S.; Jeon, Byeong-Hwa; Irani, KaikobadCirculation Research (2010), 107 (7), 877-887CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)Rationale: Low-dose acetylsalicylic acid (aspirin) is widely used in the treatment and prevention of vascular atherothrombosis. Cardiovascular doses of aspirin also reduce systemic blood pressure and improve endothelium-dependent vasorelaxation in patients with atherosclerosis or risk factors for atherosclerosis. Aspirin can acetylate proteins, other than its pharmacol. target cyclooxygenase, at lysine residues. The role of lysine acetylation in mediating the effects of low-dose aspirin on the endothelium is not known. Objective: To det. the role of lysine acetylation of endothelial nitric oxide synthase (eNOS) in the regulation of endothelial NO prodn. by low-dose aspirin and to examine whether the lysine deacetylase histone deacetylase (HDAC)3 antagonizes the effect of low-dose aspirin on endothelial NO prodn. by reversing acetylation of functionally crit. eNOS lysine residues. Methods and results: Low concns. of aspirin induce lysine acetylation of eNOS, stimulating eNOS enzymic activity and endothelial NO prodn. in a cyclooxygenase-1-independent fashion. Low-dose aspirin in vivo also increases bioavailable vascular NO in an eNOS-dependent and cyclooxygenase-1-independent manner. Low-dose aspirin promotes the binding of eNOS to calmodulin. Lysine 609 in the calmodulin autoinhibitory domain of bovine eNOS mediates aspirin-stimulated binding of eNOS to calmodulin and eNOS-derived NO prodn. HDAC3 inhibits aspirin-stimulated (1) lysine acetylation of eNOS, (2) eNOS enzymic activity, (3) eNOS-derived NO, and (4) binding of eNOS to calmodulin. Conversely, downregulation of HDAC3 promotes lysine acetylation of eNOS and endothelial NO generation. Conclusions: Lysine acetylation of eNOS is a posttranslational protein modification supporting low-dose aspirin-induced vasoprotection. HDAC3, by deacetylating aspirin-acetylated eNOS, antagonizes aspirin-stimulated endothelial prodn. of NO.
- 249Ziesché, E.; Kettner-Buhrow, D.; Weber, A.; Wittwer, T.; Jurida, L.; Soelch, J.; Müller, H.; Newel, D.; Kronich, P.; Schneider, H.; Dittrich-Breiholz, O.; Bhaskara, S.; Hiebert, S. W.; Hottiger, M. O.; Li, H.; Burstein, E.; Schmitz, M. L.; Kracht, M. The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB. Nucleic Acids Res. 2013, 41, 90– 109, DOI: 10.1093/nar/gks916[Crossref], [PubMed], [CAS], Google Scholar249https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhsFektQ%253D%253D&md5=b33a4d12e3010f3f78ac438635f16b9eThe coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κBZiesche, Elisabeth; Kettner-Buhrow, Daniela; Weber, Axel; Wittwer, Tobias; Jurida, Liane; Soelch, Johanna; Mueller, Helmut; Newel, Doris; Kronich, Petra; Schneider, Heike; Dittrich-Breiholz, Oliver; Bhaskara, Srividya; Hiebert, Scott W.; Hottiger, Michael O.; Li, Haiying; Burstein, Ezra; Schmitz, M. Lienhard; Kracht, MichaelNucleic Acids Research (2013), 41 (1), 90-109CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes contg. silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a pos. regulator of IL-1-induced gene expression. Various exptl. approaches involving RNAi-mediated knockdown, conditional gene deletion or small mol. inhibitors indicate a pos. role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-κB p65 and its deacetylation at various lysines. NF-κB p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-κB p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently obsd. for HDAC inhibitors in (pre)clin. use.
- 250Morioka, N.; Tomori, M.; Zhang, F. F.; Saeki, M.; Hisaoka-Nakashima, K.; Nakata, Y. Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cells. Biochem. Biophys. Res. Commun. 2016, 469, 151– 157, DOI: 10.1016/j.bbrc.2015.11.086[Crossref], [PubMed], [CAS], Google Scholar250https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFCltr%252FK&md5=d3c181a908f06bf5cb3bff3b8a5cb767Stimulation of nuclear receptor REV-ERBs regulates tumor necrosis factor-induced expression of proinflammatory molecules in C6 astroglial cellsMorioka, Norimitsu; Tomori, Mizuki; Zhang, Fang Fang; Saeki, Munenori; Hisaoka-Nakashima, Kazue; Nakata, YoshihiroBiochemical and Biophysical Research Communications (2016), 469 (2), 151-157CODEN: BBRCA9; ISSN:0006-291X. (Elsevier B.V.)Under physiol. conditions, astrocytes maintain homeostasis in the CNS. Following inflammation and injury to the CNS, however, activated astrocytes produce neurotoxic mols. such as cytokines and chemokines, amplifying the initial mol.-cellular events evoked by inflammation and injury. Nuclear receptors REV-ERBα and REV-ERBβ (REV-ERBs) are crucial in the regulation of inflammation- and metab.-related gene transcription. The current study sought to elucidate a role of REV-ERBs in rat C6 astroglial cells on the expression of inflammatory mols. following stimulation with the neuroinflammatory cytokine tumor necrosis factor (TNF). Stimulation of C6 cells with TNF (10 ng/mL) significantly increased the mRNA expression of CCL2, interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and matrix metalloprotease (MMP)-9, but not fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (COX-2) and MMP-2. Treatment with either REV-ERB agonists GSK4112 or SR9009 significantly blocked TNF-induced upregulation of CCL2 mRNA and MMP-9 mRNA, but not IL-6 mRNA and iNOS mRNA expression. Furthermore, treatment with RGFP966, a selective histone deacetylase 3 (HDAC3) inhibitor, potently reversed the inhibitory effects of GSK4112 on TNF-induced expression of MMP-9 mRNA, but not CCL2 mRNA. Expression of Rev-erbs mRNA in C6 astroglial cells, primary cultured rat cortical and spinal astrocytes was confirmed by reverse transcription polymerase chain reaction. Together, the findings demonstrate an anti-inflammatory effect, downregulating of MMP-9 and CCL2 transcription, of astroglial REV-ERBs activation through HDAC3-dependent and HDAC3-independent mechanisms.
- 251Leus, N. G.; van der Wouden, P. E.; van den Bosch, T.; Hooghiemstra, W. T. R.; Ourailidou, M. E.; Kistemaker, L. E.; Bischoff, R.; Gosens, R.; Haisma, H. J.; Dekker, F. J. HDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activity. Biochem. Pharmacol. 2016, 108, 58– 74, DOI: 10.1016/j.bcp.2016.03.010[Crossref], [PubMed], [CAS], Google Scholar251https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28XksVWmsrs%253D&md5=6068577165c78778170d77e4065042ecHDAC 3-selective inhibitor RGFP966 demonstrates anti-inflammatory properties in RAW 264.7 macrophages and mouse precision-cut lung slices by attenuating NF-κB p65 transcriptional activityLeus, Niek G. J.; van der Wouden, Petra E.; van den Bosch, Thea; Hooghiemstra, Wouter T. R.; Ourailidou, Maria E.; Kistemaker, Loes E. M.; Bischoff, Rainer; Gosens, Reinoud; Haisma, Hidde J.; Dekker, Frank J.Biochemical Pharmacology (Amsterdam, Netherlands) (2016), 108 (), 58-74CODEN: BCPCA6; ISSN:0006-2952. (Elsevier B.V.)The increasing no. of patients suffering from chronic obstructive pulmonary disease (COPD) represents a major and increasing health problem. Therefore, novel therapeutic approaches are needed. Class I HDACs 1, 2 and 3 play key roles in the regulation of inflammatory gene expression with a particular pro-inflammatory role for HDAC 3. HDAC 3 has been reported to be an important player in inflammation by deacetylating NF-κB p65, which has been implicated in the pathol. of COPD. Here, we applied the pharmacol. HDAC 3-selective inhibitor RGFP966, which attenuated pro-inflammatory gene expression in models for inflammatory lung diseases. Consistent with this, a robust decrease of the transcriptional activity of NF-κB p65 was obsd. HDAC 3 inhibition affected neither the acetylation status of NF-κB p65 nor histone H3 or histone H4. This indicates that HDAC 3 inhibition does not inhibit NF-κB p65 transcriptional activity by affecting its deacetylation but rather by inhibiting enzymic activity of HDAC 3. Taken together, our findings indicate that pharmacol. HDAC 3-selective inhibition by inhibitors such as RGFP966 may provide a novel and effective approach toward development of therapeutics for inflammatory lung diseases.
- 252Lin, W.; Zhang, Q.; Liu, L.; Yin, S.; Liu, Z.; Cao, W. Klotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney disease. Kidney Int. 2017, 92, 669– 679, DOI: 10.1016/j.kint.2017.02.023[Crossref], [PubMed], [CAS], Google Scholar252https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmt1Gqt74%253D&md5=44d15c7a989af6b8b0d4ea22dda216dfKlotho restoration via acetylation of Peroxisome Proliferation-Activated Receptor γ reduces the progression of chronic kidney diseaseLin, Wenjun; Zhang, Qin; Liu, Lin; Yin, Shasha; Liu, Zhihong; Cao, WangsenKidney International (2017), 92 (3), 669-679CODEN: KDYIA5; ISSN:0085-2538. (Elsevier Inc.)Klotho is an anti-aging protein mainly expressed in the kidney. Reduced Klotho (1) expression closely correlates with the development and progression of chronic kidney disease (CKD). Klotho is also a downstream gene of Peroxisome Proliferation-Activated Receptor γ (PPARγ), a major transcription factor whose functions are significantly affected by post-translational modifications including acetylation. However, whether PPARγ acetylation regulates renal Klotho expression and function in CKD is unknown. Here we test whether renal damage and reduced Klotho expression in the adenine CKD mouse model can be attenuated by the pan histone deacetylase (HDAC) inhibitor trichostatin A. This inhibition up-regulated Klotho mainly through an enhancement of PPARγ acetylation, stimulation of PPARγ binding to Klotho promoter, and PPARγ-dependent increase in Klotho transcription, with a substantial control of the regulation occurring via PPARγ acetylations on K240 and K265. Consistently trichostatin A-induced reversal of Klotho loss and renoprotective effects were abrogated in PPARγ knockout mice, supporting that PPARγ is an essential acetylation target for Klotho restoration and renal protection. Intriguingly, the kidneys of adenine-fed CKD mice displayed deregulated HDAC3 up-regulation. Selective HDAC3 inhibition effectively alleviated Klotho loss and kidney injury, whereas the protective effects were largely abolished when Klotho was knocked down by siRNA, suggesting that aberrant HDAC3 and Klotho loss are crucial components involved in the renal damage of mice with CKD. Our study identified an important signaling cascade and key components contributing to the pathogenesis of CKD. Thus, targeting Klotho loss by HDAC3 inhibition has promising therapeutic potential for the redn. of CKD progression.
- 253Zwinderman, M. R. H.; de Weerd, S.; Dekker, F. J. Targeting HDAC Complexes in Asthma and COPD. Epigenomes 2019, 3, 19, DOI: 10.3390/epigenomes3030019[Crossref], [CAS], Google Scholar253https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitFyr&md5=797188345106298228cf9cd061721ff3Targeting HDAC complexes in asthma and COPDZwinderman, Martijn R. H.; de Weerd, Sander; Dekker, Frank J.Epigenomes (2019), 3 (3), 19CODEN: EPIGD8; ISSN:2075-4655. (MDPI AG)A review. Around three million patients die due to airway inflammatory diseases each year. The most notable of these diseases are asthma and chronic obstructive pulmonary disease (COPD). Therefore, new therapies are urgently needed. Promising targets are histone deacetylases (HDACs), since they regulate posttranslational protein acetylation. Over a thousand proteins are reversibly acetylated, and acetylation critically influences aberrant intracellular signaling pathways in asthma and COPD. The diverse set of selective and non-selective HDAC inhibitors used in pre-clin. models of airway inflammation show promising results, but several challenges still need to be overcome. One such challenge is the design of HDAC inhibitors with unique selectivity profiles, such as selectivity towards specific HDAC complexes. Novel strategies to disrupt HDAC complexes should be developed to validate HDACs further as targets for new anti-inflammatory pulmonary treatments.
- 254Bougdour, A.; Maubon, D.; Baldacci, P.; Ortet, P.; Bastien, O.; Bouillon, A.; Barale, J. C.; Pelloux, H.; Ménard, R.; Hakimi, M. A. Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. J. Exp. Med. 2009, 206, 953– 966, DOI: 10.1084/jem.20082826[Crossref], [PubMed], [CAS], Google Scholar254https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXkvVSiu7c%253D&md5=67adb9644c32d6e568fc64685394fe75Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasitesBougdour, Alexandre; Maubon, Daniele; Baldacci, Patricia; Ortet, Philippe; Bastien, Olivier; Bouillon, Anthony; Barale, Jean-Christophe; Pelloux, Herve; Menard, Robert; Hakimi, Mohamed-AliJournal of Experimental Medicine (2009), 206 (4), 953-966CODEN: JEMEAV; ISSN:0022-1007. (Rockefeller University Press)Plasmodium and Toxoplasma are parasites of major medical importance that belong to the Apicomplexa phylum of protozoa. These parasites transform into various stages during their life cycle and express a specific set of proteins at each stage. Although little is yet known of how gene expression is controlled in Apicomplexa, histone modifications, particularly acetylation, are emerging as key regulators of parasite differentiation and stage conversion. We investigated the anti-Apicomplexa effect of FR235222, a histone deacetylase inhibitor (HDACi). We show that FR235222 is active against a variety of Apicomplexa genera, including Plasmodium and Toxoplasma, and is more potent than other HDACi's such as trichostatin A and the clin. relevant compd. pyrimethamine. We identify T. gondii HDAC3 (TgHDAC3) as the target of FR235222 in Toxoplasma tachyzoites and demonstrate the crucial role of the conserved and Apicomplexa HDAC-specific residue TgHDAC3 T99 in the inhibitory activity of the drug. We also show that FR235222 induces differentiation of the tachyzoite (replicative) into the bradyzoite (nonreplicative) stage. Addnl., via its anti-TgHDAC3 activity, FR235222 influences the expression of ∼370 genes, a third of which are stage-specifically expressed. These results identify FR235222 as a potent HDACi of Apicomplexa, and establish HDAC3 as a central regulator of gene expression and stage conversion in Toxoplasma and, likely, other Apicomplexa.
- 255Zhou, Y.; Wang, Q.; Yang, Q.; Tang, J.; Xu, C.; Gai, D.; Chen, X.; Chen, J. Histone deacetylase 3 inhibitor suppresses hepatitis C virus replication by regulating Apo-A1 and LEAP-1 expression. Virol. Sin. 2018, 33, 418– 428, DOI: 10.1007/s12250-018-0057-7[Crossref], [PubMed], [CAS], Google Scholar255https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhvFKjt7bI&md5=439a3b8dc0e7c0fa854ef4c996883911Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 ExpressionZhou, Yuan; Wang, Qian; Yang, Qi; Tang, Jielin; Xu, Chonghui; Gai, Dongwei; Chen, Xinwen; Chen, JizhengVirologica Sinica (2018), 33 (5), 418-428CODEN: VSIICH; ISSN:1674-0769. (Springer GmbH)Histone deacetylase (HDAC) inhibitors show clin. promise for the treatment of cancers, including hepatocellular carcinoma (HCC). In this study, we investigated the effect of HDAC inhibitor treatment on hepatitis C virus (HCV) replication in Huh7 human liver cells and in a mouse model of HCV infection. Viral replication was markedly suppressed by the HDAC3 inhibitor at concns. below 1 mmol/L, with no cellular toxicity. This was accompanied by upregulation of liver-expressed antimicrobial peptide 1(LEAP-1) and downregulation of apolipoprotein-A1 (Apo-A1), as detd. by microarray and quant. RT-PCR analyses. Moreover, HDAC3 was found to modulate the binding of CCAAT-enhancer-binding protein α (C/EBPα), hypoxia-inducible factor 1α (HIF1α), and signal transducer and activator of transcription 3 (STAT3) to the LEAP-1 promoter. HDAC3 inhibitor treatment also blocked HCV replication in a mouse model of HCV infection. These results indicate that epigenetic therapy with HDAC3 inhibitor may be a potential treatment for diseases assocd. with HCV infection such as HCC.
- 256Villanueva, R.; Iglesias, A. H.; Camelo, S.; Sanin, L. C.; Gray, S. G.; Dangond, F. Histone deacetylase 3 represses HTLV-1 tax transcription. Oncol. Rep. 2006, 16, 581– 585, DOI: 10.3892/or.16.3.581[Crossref], [PubMed], [CAS], Google Scholar256https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD28XptVagsLs%253D&md5=d1e7cff1fd10d1afe83e4e22d65def2eHistone deacetylase 3 represses HTLV-1 tax transcriptionVillanueva, Raul; Iglesias, Antonio H.; Camelo, Sandra; Sanin, Luis C.; Gray, Steven G.; Dangond, FernandoOncology Reports (2006), 16 (3), 581-585CODEN: OCRPEW; ISSN:1021-335X. (Oncology Reports)We examd. the epigenetic mechanisms involved in human T-cell lymphotropic virus type 1 (HTLV-1) Tax expression. Blockade of histone deacetylation with trichostatin A (TSA) resulted in Tax upregulation. Using a chromatin immunopptn. (ChIP) assay, we verified local histone hyperacetylation at the HTLV-1 LTR in response to TSA. In agreement, HDAC3 transfection led to redns. in both Tax expression and histone acetylation. HDAC3 mutations and deletions spanning the catalytic site had variable ability to repress Tax, but HDAC activity was not essential for repression. Immunopptn. studies revealed that Tax co-exists in a complex contg. both histone deacetylase 1 (HDAC1) and 3 (HDAC3). Our results suggest that HDACs may actively participate in the repression of HTLV-1 Tax transcription.
- 257Barton, K. M.; Archin, N. M.; Keedy, K. S.; Espeseth, A. S.; Zhang, Y. L.; Gale, J.; Wagner, F. F.; Holson, E. B.; Margolis, D. M. Selective HDAC inhibition for the disruption of latent HIV-1 infection. PLoS One 2014, 9, e102684 DOI: 10.1371/journal.pone.0102684[Crossref], [PubMed], [CAS], Google Scholar257https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhs1CisrbM&md5=d967dbe2a9b6004029ded4b8cad2f657Selective HDAC inhibition for the disruption of latent HIV-1 infectionBarton, Kirston M.; Archin, Nancie M.; Keedy, Kara S.; Espeseth, Amy S.; Zhang, Yan-Ling; Gale, Jennifer; Wagner, Florence F.; Holson, Edward B.; Margolis, David M.PLoS One (2014), 9 (8), e102684/1-e102684/11, 11 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)Selective histone deacetylase (HDAC) inhibitors have emerged as a potential anti-latency therapy for persistent human immunodeficiency virus type 1 (HIV-1) infection. We utilized a combination of small mol. inhibitors and short hairpin (sh)RNA-mediated gene knockdown strategies to delineate the key HDAC(s) to be targeted for selective induction of latent HIV-1 expression. Individual depletion of HDAC3 significantly induced expression from the HIV-1 promoter in the 2D10 latency cell line model. However, depletion of HDAC1 or -2 alone or in combination did not significantly induce HIV-1 expression. Co-depletion of HDAC2 and -3 resulted in a significant increase in expression from the HIV-1 promoter. Furthermore, concurrent knockdown of HDAC1, -2, and -3 resulted in a significant increase in expression from the HIV-1 promoter. Using small mol. HDAC inhibitors of differing selectivity to ablate the residual HDAC activity that remained after (sh)RNA depletion, the effect of depletion of HDAC3 was further enhanced. Enzymic inhibition of HDAC3 with the selective small-mol. inhibitor BRD3308 activated HIV-1 transcription in the 2D10 cell line. Furthermore, ex vivo exposure to BRD3308 induced outgrowth of HIV-1 from resting CD4+ T cells isolated from antiretroviral-treated, aviremic HIV+ patients. Taken together these findings suggest that HDAC3 is an essential target to disrupt HIV-1 latency, and inhibition of HDAC2 may also contribute to the effort to purge and eradicate latent HIV-1 infection.
- 258Choudhary, V.; Olala, L. O.; Kagha, K.; Pan, Z. Q.; Chen, X.; Yang, R.; Cline, A.; Helwa, I.; Marshall, L.; Kaddour-Djebbar, I.; McGee-Lawrence, M. E.; Bollag, W. B. Regulation of the glycerol transporter, Aquaporin-3, by histone deacetylase-3 and p53 in keratinocytes. J. Invest. Dermatol. 2017, 137, 1935– 1944, DOI: 10.1016/j.jid.2017.04.031[Crossref], [PubMed], [CAS], Google Scholar258https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1WgurbM&md5=731c8746e34108da3f8c3044181d73e5Regulation of the Glycerol Transporter, Aquaporin-3, by Histone Deacetylase-3 and p53 in KeratinocytesChoudhary, Vivek; Olala, Lawrence O.; Kagha, Karen; Pan, Zhi-qiang; Chen, Xunsheng; Yang, Rong; Cline, Abigail; Helwa, Inas; Marshall, Lauren; Kaddour-Djebbar, Ismail; McGee-Lawrence, Meghan E.; Bollag, Wendy B.Journal of Investigative Dermatology (2017), 137 (9), 1935-1944CODEN: JIDEAE; ISSN:0022-202X. (Elsevier Inc.)Aquaporin- (AQP) 3, a water and glycerol channel, plays an important role in epidermal function, with studies showing its involvement in keratinocyte proliferation, differentiation, and migration and in epidermal wound healing and barrier repair. Increasing speculation about the use of histone deacetylase (HDAC) inhibitors to treat skin diseases led us to investigate HDAC's role in the regulation of AQP3. The broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid induced AQP3 mRNA and protein expression in a dose- and time-dependent manner in normal keratinocytes. The SAHA-induced increase in AQP3 levels resulted in enhanced [3H]glycerol uptake in normal but not in AQP3-knockout keratinocytes, confirming that the expressed AQP3 was functional. Use of HDAC inhibitors with different specificities limited our exploration of the responsible HDAC member to HDAC1, HDAC2, or HDAC3. Cre-recombinase-mediated knockdown and overexpression of HDAC3 suggested a role for HDAC3 in suppressing AQP3 expression basally. Further investigation implicated p53 as a transcription factor involved in regulating HDAC inhibitor-induced AQP3 expression. Thus, our study supports the regulation of AQP3 expression by HDAC3 and p53. Because suberoylanilide hydroxamic acid is already approved to treat cutaneous T-cell lymphoma, it could potentially be used as a therapy for skin diseases like psoriasis, where AQP3 is abnormally expressed.
- 259Kim, Y.; Kim, K.; Park, D.; Lee, E.; Lee, H.; Lee, Y. S.; Choe, J.; Jeoung, D. Histone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 protein. J. Biol. Chem. 2012, 287, 25844– 25859, DOI: 10.1074/jbc.M112.348284[Crossref], [PubMed], [CAS], Google Scholar259https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2ns7vL&md5=b0858b39b22e4acbe5e56be06de1670aHistone deacetylase 3 mediates allergic skin inflammation by regulating expression of MCP1 proteinKim, Youngmi; Kim, Kyungjong; Park, Deokbum; Lee, Eunmi; Lee, Hansoo; Lee, Yun-Sil; Choe, Jongseon; Jeoung, DooilJournal of Biological Chemistry (2012), 287 (31), 25844-25859CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)We have shown the induction of histone deacetylase 3 (HDAC3) in antigen-stimulated rat basophilic leukemia cells via NF-κB. We investigated the role of HDAC3 in allergic skin inflammation. We used a BALB/c mouse model of triphasic cutaneous anaphylaxis (triphasic cutaneous reaction; TpCR) and passive cutaneous anaphylaxis (PCA) to examine the role of HDAC3 in allergic skin inflammation. Triphasic cutaneous reaction involved induction of HDAC3 and was mediated by HDAC3. HDAC3 showed an interaction with FcεRIβ. Trichostatin A (TSA), an inhibitor of HDAC(s), disrupted this interaction. Cytokine array anal. showed that the down-regulation of HDAC3 led to the decreased secretion of monocyte chemoattractant protein 1 (MCP1). FcεRI was necessary for induction of HDAC3 and MCP1. ChIP assays showed that HDAC3, in assocn. with Sp1 and c-Jun, was responsible for induction of MCP1 expression. TSA exerted a neg. effect on induction of MCP1. HDAC3 exerted a neg. regulation on expression of HDAC2 via interaction with Rac1. The down-regulation of HDAC3 or inactivation of Rac1 induced binding of HDAC2 to MCP1 promoter sequences. TSA exerted a neg. effect on HDAC3-mediated TpCR. The BALB/c mouse model of PCA involved induction of HDAC3 and MCP1. HDAC3 and MCP1 were necessary for PCA that involved ear swelling, enhanced vascular permeability, and angiogenesis. Recombinant MCP1 enhanced β-hexosaminidase activity and histamine release and also showed angiogenic potential. TSA exerted a neg. effect on PCA. Our data show HDAC3 as a valuable target for the development of allergic skin inflammation therapeutics.
- 260Kim, Y.; Kim, K.; Park, D.; Lee, E.; Lee, H.; Lee, Y. S.; Choe, J.; Kim, Y. M.; Jeoung, D. DNA methyl transferase I acts as a negative regulator of allergic skin inflammation. Mol. Immunol. 2013, 53, 1– 14, DOI: 10.1016/j.molimm.2012.06.010[Crossref], [PubMed], [CAS], Google Scholar260https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtlaiurfP&md5=143c3a50810d410f6e498c6ca9240949DNA methyl transferase I acts as a negative regulator of allergic skin inflammationKim, Youngmi; Kim, Kyungjong; Park, Deokbum; Lee, Eunmi; Lee, Hansoo; Lee, Yun-Sil; Choe, Jongseon; Kim, Young-Myeong; Jeoung, DooilMolecular Immunology (2013), 53 (1-2), 1-14CODEN: MOIMD5; ISSN:0161-5890. (Elsevier)The role of DNA Me transferase I (DNMT1) in allergic inflammation was investigated. Antigen stimulation decreased expression of DNMT1 in rat basophilic leukemia cells (RBL2H3). The down regulation of DNMT1 induced expression of histone deacetylase 3 (HDAC3). HDAC3 was necessary for allergic skin inflammation, such as such as triphasic cutaneous reaction and passive cutaneous anaphylaxis. The down regulation of DNMT1 resulted from activation of PKC and rac1 which were necessary for proteasome-dependent ubiquitination of DNMT1 by antigen stimulation. N-acetyl-L-cysteine, an inhibitor of reactive oxygen species prodn., exerted neg. effects on allergic skin inflammation. Antigen stimulation led to increased expression of Tip60, a histone acetyl transferase. Wild type, but not mutant form, Tip60 decreased expression of DNMT1 while increasing expression of HDAC3, suggesting role for acetylation in ubiquitin-dependent proteasomal degrdn. of DNMT1. In vivo down regulation of DNMT1 increased ear thickness, typical of allergic skin inflammation, induced vascular leakage and promoted angiogenesis in BALB/c mouse. The down regulation of DNMT1 enhanced angiogenic potential of rat aortic endothelial cells (RAEC) accompanied by activation of VEGFR-2 and induced interaction between VEGFR-2 and syk in RAEC. The enhanced angiogenic potential of RAEC was assocd. with the induction of VEGF by down regulation of DNMT1 in RBL2H3 cells. The down regulation of DNMT1 induced leukocytes-endothelial cell interaction and expression of various adhesion mols. Aspirin exerted a neg. effect on allergic skin inflammation by indirect regulation on DNMT1 via Tip60. Taken together, these results suggest novel role for DNMT1 in allergic skin inflammation.
- 261Kim, Y.; Eom, S.; Kim, K.; Lee, Y. S.; Choe, J.; Hahn, J. H.; Lee, H.; Kim, Y. M.; Ha, K. S.; Ro, J. Y.; Jeoung, D. Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammation. Mol. Immunol. 2010, 47, 1010– 1022, DOI: 10.1016/j.molimm.2009.11.017[Crossref], [PubMed], [CAS], Google Scholar261https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXpsFKrtw%253D%253D&md5=4828dda2d1152af6c55dd1d462cf6784Transglutaminase II interacts with rac1, regulates production of reactive oxygen species, expression of snail, secretion of Th2 cytokines and mediates in vitro and in vivo allergic inflammationKim, Youngmi; Eom, Sangkyung; Kim, Kyungjong; Lee, Yun-Sil; Choe, Jongseon; Hahn, Jang Hee; Lee, Hansoo; Kim, Young-Myeong; Ha, Kwon Soo; Ro, Jai Youl; Jeoung, DooilMolecular Immunology (2010), 47 (5), 1010-1022CODEN: MOIMD5; ISSN:0161-5890. (Elsevier Ltd.)Transglutaminase II (TGase II) is a protein crosslinking enzyme with diverse biol. functions. Here the authors report the role of TGase II in allergic inflammation. Antigen stimulation induced expression and activity of TGase II by activation of NF-κB in rat basophilic leukemia (RBL2H3) cells. This induction of TGase II was dependent on FcεRI and EGFR. Interaction between TGase II and rac1 was induced following antigen stimulation. TGase II was responsible for the increased prodn. of reactive oxygen species, expression of prostaglandin E2 synthase (PGE2 synthase) and was responsible for increased secretion of prostaglandin E2. ChIP assay showed that TGase II, through interaction with NF-κB, was responsible for the induction of histone deacetylase-3 (HDAC3) and snail by direct binding to promoter sequences. HDAC3 and snail induced by TGase II, exerted transcriptional repression on E-cadherin. Snail exerted neg. effect on expression of MMP-2, and secretion of Th2 cytokines. Inhibition of matrix metalloproteinase-2 (MMP-2) inhibited secretion of Th2 cytokines. In vivo induction of TGase II was obsd. in Balb/c mouse model of IgE antibody-induced passive cutaneous anaphylaxis. Chem. inhibition of TGase II exerted neg. effect on IgE-dependent passive cutaneous anaphylaxis. Chem. inhibition of TGase II by cystamine exerted neg. effect on Balb/c mouse model of phorbol myristate acetate (PMA)-induced atopic dermatitis. These results suggest novel role of TGase II in allergic inflammation and TGase II can be developed as target for the development of allergy therapeutics.
- 262Shu, J.; Li, L.; Zhou, L. B.; Qian, J.; Fan, Z. D.; Zhuang, L. L.; Wang, L. L.; Jin, R.; Yu, H. G.; Zhou, G. P. IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitors. Oncotarget 2017, 8, 47184– 47194, DOI: 10.18632/oncotarget.17586[Crossref], [PubMed], [CAS], Google Scholar262https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADC%252BC1crptlymsg%253D%253D&md5=b4eda1d9e7bf2e20c0b2e1b9beef5794IRF5 is elevated in childhood-onset SLE and regulated by histone acetyltransferase and histone deacetylase inhibitorsShu Jin; Li Ling; Qian Jun; Zhou Lan-Bo; Fan Zhi-Dan; Yu Hai-Guo; Zhuang Li-Li; Wang Lu-Lu; Jin Rui; Zhou Guo-PingOncotarget (2017), 8 (29), 47184-47194 ISSN:.Interferon regulatory factor 5 (IRF5) plays a critical role in the induction of type I interferon, proinflammatory cytokines and chemokines, and participates in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). However, the relationship between IRF5 and childhood-onset SLE remains elusive. In the present study, we demonstrated that levels of mRNA expression of IRF5, IFN-α, and Sp1 were significantly increased in childhood-onset SLE, as seen on quantitative real-time PCR, and the expression of Sp1 and IFN-α was positively correlated with IRF5. In addition to being used as antitumor drugs, a number of histone deacetylase inhibitors (HDACi) display potent anti-inflammatory properties; however, their effects on IRF5 expression remain unclear. In this study, we identified that HDACi trichostatin A (TSA) and histone acetyltransferase (HAT)-p300 downregulated IRF5 promoter activity, mRNA expression, and protein level, whereas the HAT-p300/CBP-associated factor had no effect. Moreover, TSA inhibited the production of TNF-α and IL-6 in differentiated THP-1cells. Furthermore, chromatin immunoprecipitation assays revealed that TSA inhibited DNA binding of Sp1, RNA polymerase II, HDAC3, and p300 to the core promoter region of IRF5. Our results suggest that HDACi may have therapeutic potential in patients with autoimmune diseases such as SLE through repression of IRF5 expression.
- 263Hannan, J. L.; Kutlu, O.; Stopak, B. L.; Liu, X.; Castiglione, F.; Hedlund, P.; Burnett, A. L.; Bivalacqua, T. J. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats. J. Sex. Med. 2014, 11, 1442– 1451, DOI: 10.1111/jsm.12522[Crossref], [PubMed], [CAS], Google Scholar263https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXps1Wjs74%253D&md5=01fa374d516b0cac34faef280bb529bcValproic Acid Prevents Penile Fibrosis and Erectile Dysfunction in Cavernous Nerve-Injured RatsHannan, Johanna L.; Kutlu, Omer; Stopak, Bernard L.; Liu, Xiaopu; Castiglione, Fabio; Hedlund, Petter; Burnett, Arthur L.; Bivalacqua, Trinity J.Journal of Sexual Medicine (2014), 11 (6), 1442-1451CODEN: JSMOAN; ISSN:1743-6095. (Wiley-Blackwell)Introduction : Bilateral cavernous nerve injury (BCNI) causes profound penile changes such as apoptosis and fibrosis leading to erectile dysfunction (ED). Histone deacetylase (HDAC) has been implicated in chronic fibrotic diseases. Aims : This study will characterize the mol. changes in penile HDAC after BCNI and det. if HDAC inhibition can prevent BCNI-induced ED and penile fibrosis. Methods : Five groups of rats (8-10 wk, n = 10/group) were utilized: (i) sham; (ii and iii) BCNI 14 and 30 days following injury; and (iv and v) BCNI treated with HDAC inhibitor valproic acid (VPA 250 mg/kg; 14 and 30 days). All groups underwent cavernous nerve stimulation (CNS) to det. intracavernosal pressure (ICP). Penile HDAC3, HDAC4, fibronectin, and transforming growth factor-β1 (TGF-β1) protein expression (Western blot) were assessed. Trichrome staining and the fractional area of fibrosis were detd. in penes from each group. Cavernous smooth muscle content was assessed by immunofluorescence to alpha smooth muscle actin (α-SMA) antibodies. Main Outcome Measures : We measured ICP; HDAC3, HDAC4, fibronectin, and TGF-β1 protein expression; penile fibrosis; penile α-SMA content. Results : There was a voltage-dependent decline (P < 0.05) in ICP to CNS 14 and 30 days after BCNI. Penile HDAC3, HDAC4, and fibronectin were significantly increased (P < 0.05) 14 days after BCNI. There was a slight increase in TGF-β1 protein expression after BCNI. Histol. anal. showed increased (P < 0.05) corporal fibrosis after BCNI at both time points. VPA treatment decreased (P < 0.05) penile HDAC3, HDAC4, and fibronectin protein expression as well as corporal fibrosis. There was no change in penile α-SMA between all groups. Furthermore, VPA-treated BCNI rats had improved erectile responses to CNS (P < 0.05). Conclusion : HDAC-induced pathol. signaling in response to BCNI contributes to penile vascular dysfunction. Pharmacol. inhibition of HDAC prevents penile fibrosis, normalizes fibronectin expression, and preserves erectile function. The HDAC pathway may represent a suitable target in preventing the progression of ED occurring post-radical prostatectomy. Hannan JL, Kutlu O, Stopak BL, Liu X, Castiglione F, Hedlund P, Burnett AL, and Bivalacqua TJ. Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats.
- 264Tapadar, S.; He, R.; Luchini, D. N.; Billadeau, D. D.; Kozikowski, A. P. Isoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: effects on HDAC biology and antiproliferative activity. Bioorg. Med. Chem. Lett. 2009, 19, 3023– 3026, DOI: 10.1016/j.bmcl.2009.04.058[Crossref], [PubMed], [CAS], Google Scholar264https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXmtVersrs%253D&md5=affc37e7890fc939db595fa48397390cIsoxazole moiety in the linker region of HDAC inhibitors adjacent to the Zn-chelating group: Effects on HDAC biology and antiproliferative activityTapadar, Subhasish; He, Rong; Luchini, Doris N.; Billadeau, Daniel D.; Kozikowski, Alan P.Bioorganic & Medicinal Chemistry Letters (2009), 19 (11), 3023-3026CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)A series of hydroxamic acid based histone deacetylase inhibitors 6-15, contg. an isoxazole moiety adjacent to the Zn-chelating hydroxamic acid, is reported herein. Some of these compds. showed nanomolar activity in the HDAC isoform inhibitory assay and exhibited micromolar inhibitory activity against five pancreatic cancer cell lines.
- 265Neelarapu, R.; Holzle, D. L.; Velaparthi, S.; Bai, H.; Brunsteiner, M.; Blond, S. Y.; Petukhov, P. A. Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole- and pyrazole-based histone deacetylase probes. J. Med. Chem. 2011, 54, 4350– 4364, DOI: 10.1021/jm2001025[ACS Full Text], [CAS], Google Scholar265https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXntVemsbw%253D&md5=274a01467ab7108b87dd6634562f4635Design, Synthesis, Docking, and Biological Evaluation of Novel Diazide-Containing Isoxazole- and Pyrazole-Based Histone Deacetylase ProbesNeelarapu, Raghupathi; Holzle, Denise L.; Velaparthi, Subash; Bai, He; Brunsteiner, Michael; Blond, Sylvie Y.; Petukhov, Pavel A.Journal of Medicinal Chemistry (2011), 54 (13), 4350-4364CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The design, synthesis, docking, and biol. evaluation of novel potent HDAC3 and HDAC8 isoxazole- and pyrazole-based diazide probes suitable for binding ensemble profiling with photoaffinity labeling (BEProFL) expts. in cells is described. Both the isoxazole- and pyrazole-based probes exhibit low nanomolar inhibitory activity against HDAC3 and HDAC8, resp. The pyrazole-based probe I appears to be one of the most active HDAC8 inhibitors reported in the literature with an IC50 of 17 nM. Our docking studies suggest that unlike the isoxazole-based ligands the pyrazole-based ligands are flexible enough to occupy the second binding site of HDAC8. Probes/inhibitors II, III (R = H, N3) and I exerted the antiproliferative and neuroprotective activities at micromolar concns. through inhibition of nuclear HDACs, indicating that they are cell permeable and the presence of an azide or a diazide group does not interfere with the neuroprotection properties, or enhance cellular cytotoxicity, or affect cell permeability.
- 266Thaler, F.; Varasi, M.; Abate, A.; Carenzi, G.; Colombo, A.; Bigogno, C.; Boggio, R.; Zuffo, R. D.; Rapetti, D.; Resconi, A.; Regalia, N.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C. Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors. Eur. J. Med. Chem. 2013, 64, 273– 284, DOI: 10.1016/j.ejmech.2013.03.061[Crossref], [PubMed], [CAS], Google Scholar266https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXptFOntbs%253D&md5=3269d95992f1ede24d84b185624f04d6Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] based histone deacetylase inhibitorsThaler, Florian; Varasi, Mario; Abate, Agnese; Carenzi, Giacomo; Colombo, Andrea; Bigogno, Chiara; Boggio, Roberto; Dal Zuffo, Roberto; Rapetti, Daniela; Resconi, Anna; Regalia, Nickolas; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, CiroEuropean Journal of Medicinal Chemistry (2013), 64 (), 273-284CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Histone deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies the authors described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, the authors report further explorations, which resulted in the discovery of a new class of spiro-benzoxazinepiperidines I [R = H, Me, Bn, etc., R1 = H, Me, Bn]. Several compds. showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumor cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumor growth inhibition. In addn., the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogs.
- 267Thaler, F.; Varasi, M.; Carenzi, G.; Colombo, A.; Abate, A.; Bigogno, C.; Boggio, R.; Carrara, S.; Cataudella, T.; Dal Zuffo, R.; Reali, V.; Vultaggio, S.; Dondio, G.; Gagliardi, S.; Minucci, S.; Mercurio, C. ChemMedChem 2012, 7, 709– 721, DOI: 10.1002/cmdc.201200024[Crossref], [PubMed], [CAS], Google Scholar267https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XisFyis7w%253D&md5=b1a34d6dfb56c2919cd560f64acb726aSpiro[chromane-2,4'-piperidine]-Based Histone Deacetylase Inhibitors with Improved in vivo ActivityThaler, Florian; Varasi, Mario; Carenzi, Giacomo; Colombo, Andrea; Abate, Agnese; Bigogno, Chiara; Boggio, Roberto; Carrara, Simone; Cataudella, Tiziana; Dal Zuffo, Roberto; Reali, Veronica; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, CiroChemMedChem (2012), 7 (4), 709-721CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of spiro[chromane-2,4'-piperidine] derivs. based on a previously published lead benzyl spirocycle (I) and bearing various N-aryl and N-alkylaryl substituents on the piperidine ring were prepd. as novel histone deacetylase (HDAC) inhibitors. The compds. were evaluated for their abilities to inhibit nuclear HDACs, their in vitro antiproliferative activities, and in vitro ADME profiles. Based on these activities, 4-fluorobenzyl and 2-phenylethyl spirocycles were selected for further characterization. In vivo pharmacokinetic (PK) studies showed that both compds. exhibit an overall lower clearance rate, an increased half-life, and higher AUCs after i.v. and oral administration than spiropiperidine (I) under the conditions used. The improved PK behavior of these two compds. also correlated with superior in vivo antitumor activity in an HCT-116 xenograft model.
- 268Thaler, F.; Moretti, L.; Amici, R.; Abate, A.; Colombo, A.; Carenzi, G.; Fulco, M. C.; Boggio, R.; Dondio, G.; Gagliardi, S.; Minucci, S.; Sartori, L.; Varasi, M.; Mercurio, C. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. Eur. J. Med. Chem. 2016, 108, 53– 67, DOI: 10.1016/j.ejmech.2015.11.010[Crossref], [PubMed], [CAS], Google Scholar268https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhvFantLjK&md5=1433be1e457ff6227bc42bec6241b974Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitorsThaler, Florian; Moretti, Loris; Amici, Raffaella; Abate, Agnese; Colombo, Andrea; Carenzi, Giacomo; Fulco, Maria Carmela; Boggio, Roberto; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Sartori, Luca; Varasi, Mario; Mercurio, CiroEuropean Journal of Medicinal Chemistry (2016), 108 (), 53-67CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)In the last decades, inhibitors of histone deacetylases (HDAC) have become an important class of anti-cancer agents. In a previous study we described the synthesis of spiro[chromane-2,4'-piperidine]hydroxamic acid derivs. able to inhibit histone deacetylase enzymes. Herein, we present our exploration for new derivs., e.g., I, by replacing the piperidine moiety with various cycloamines. The goal was to obtain highly potent compds. with a good in vitro ADME profile. In addn., mol. modeling studies unravelled the binding mode of these inhibitors.
- 269Choi, C. J.; Kim, M.; Han, S. Y.; Jeon, J.; Lee, J. H.; Oh, J. I.; Suh, K. H.; Suh, D. C.; Lee, K. O. Discovery of a Novel HDAC3 selective inhibitor and its evaluation in lymphoma model. Bull. Korean Chem. Soc. 2016, 37, 42– 47, DOI: 10.1002/bkcs.10619[Crossref], [CAS], Google Scholar269https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVCltL3O&md5=f439ffafc6f8468139355fbf46606434Discovery of a Novel HDAC3 Selective Inhibitor and its Evaluation in Lymphoma ModelChoi, Chang-Ju; Kim, Mira; Han, Sun Young; Jeon, Jiyoung; Lee, Jae Ho; Oh, Jeong-In; Suh, Kwee Hyun; Suh, Dong-Churl; Lee, Kwang-OkBulletin of the Korean Chemical Society (2016), 37 (1), 42-47CODEN: BKCSDE; ISSN:0253-2964. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylase (HDAC) inhibition is a potentially attractive approach to cancer therapy. A no. of HDAC inhibitors are in clin. development stages for the treatment of cancer as well as immune and inflammatory disorders. Although there are several approved HDAC inhibitors by the US FDA, they show a broad inhibitory spectrum against HDAC subfamily. Herein, we synthesized a series of novel hydroxamate analogs, and evaluated them with lymphoma cancer cell. Conclusively, we identified an HDAC3 selective inhibitor which shows good anticancer activity for the lymphoma model, as well as a good drug metab. and pharmacokinetics (DMPK) profile.
- 270Zang, J.; Shi, B.; Liang, X.; Gao, Q.; Xu, W.; Zhang, Y. Development of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activity. Bioorg. Med. Chem. 2017, 25, 2666– 2675, DOI: 10.1016/j.bmc.2016.12.001[Crossref], [PubMed], [CAS], Google Scholar270https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXkvVSlur8%253D&md5=8ce20c262f96079fa20d9e48ddc02a3bDevelopment of N-hydroxycinnamamide-based HDAC inhibitors with improved HDAC inhibitory activity and in vitro antitumor activityZang, Jie; Shi, Baowen; Liang, Xuewu; Gao, Qianwen; Xu, Wenfang; Zhang, YingjieBioorganic & Medicinal Chemistry (2017), 25 (9), 2666-2675CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)Histone deacetylase inhibitors (HDACIs) are promising in the treatment of various diseases, among which cancer treatment has achieved the most success. We have previously developed series of HDACIs combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment, which showed moderate to potent antitumor activities. Herein, further structural derivatization based on our previous structure-activity relationship (SAR) got 25 novel compds. Most compds. showed much more potent histone deacetylases (HDACs) inhibitory activity than their parent compd. 1 and even the pos. control SAHA. What's more, compared with the approved HDACs inhibitor SAHA, compds. 6i, 6k, 6q and 6t displayed better in vitro antiproliferation against multiple tumor cell lines. It is worth noting that though the 4-hydroxycinnamic acid-based compd. 2 showed HDAC1/3 dual selectivity, its 4-hydroxy-3-methoxycinnamic acid-based analog 6t turned out to be a pan-HDACs inhibitor as SAHA, indicating that the 3-methoxy group on the N-hydroxycinnamamide fragment could dramatically influence the HDACs isoform selectivity of this series of compds.
- 271Cheng, G.; Wang, Z.; Yang, J.; Bao, Y.; Xu, Q.; Zhao, L.; Liu, D. Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agents. Bioorg. Chem. 2019, 84, 410– 417, DOI: 10.1016/j.bioorg.2018.12.011[Crossref], [PubMed], [CAS], Google Scholar271https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFaqtb%252FI&md5=e2c81b5d67fd9f49e6805c6b544438b4Design, synthesis and biological evaluation of novel indole derivatives as potential HDAC/BRD4 dual inhibitors and anti-leukemia agentsCheng, Gaoliang; Wang, Zhi; Yang, Jinyu; Bao, Yu; Xu, Qihao; Zhao, Linxiang; Liu, DanBioorganic Chemistry (2019), 84 (), 410-417CODEN: BOCMBM; ISSN:0045-2068. (Elsevier B.V.)HDAC inhibitors and BRD4 inhibitors were considered to be potent anti-cancer agents. Recent studies have demonstrated that HDAC and BRD4 participate in the regulation of some signal paths like PI3K-AKT. In this work, a series of indole derivs. that combine the inhibitory activities of BRD4 and HDAC into one mol. were designed and synthesized through the structure-based design method. Most compds. showed potent HDAC inhibitory activity and moderate BRD4 inhibitory activity. In vitro anti-proliferation activities of the synthesized compds. were also evaluated. Among them, 19f was the most potent inhibitor against HDAC3 with IC50 value of 5 nM and BRD4 inhibition rate of 88% at 10 μM. It was confirmed that 19f could up-regulate the expression of Ac-H3 and reduce the expression of c-Myc by western blot anal. These results indicated that 19f was a potent dual HDAC/BRD4 inhibitor and deserved further investigation.
- 272Chen, Y.; He, R.; Chen, Y.; D’Annibale, M. A.; Langley, B.; Kozikowski, A. P. Studies of benzamide- and thiol-based histone deacetylase inhibitors in models of oxidative-stress-induced neuronal death: identification of some HDAC3-selective inhibitors. ChemMedChem 2009, 4, 842– 852, DOI: 10.1002/cmdc.200800461[Crossref], [PubMed], [CAS], Google Scholar272https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXls1KgsbY%253D&md5=38ef2bc8efbc71d2d5b6d195da49c35dStudies of Benzamide- and Thiol-Based Histone Deacetylase Inhibitors in Models of Oxidative-Stress-Induced Neuronal Death: Identification of Some HDAC3-Selective InhibitorsChen, Yufeng; He, Rong; Chen, Yihua; D'Annibale, Melissa A.; Langley, Brett; Kozikowski, Alan P.ChemMedChem (2009), 4 (5), 842-852CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Less stress: We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. Novel benzamide-based ligands selectively inhibit HDAC3 but provide no neuroprotection in the HCA-cortical neuron model of oxidative stress. We compare three structurally different classes of histone deacetylase (HDAC) inhibitors that contain benzamide, hydroxamate, or thiol groups as the zinc binding group (ZBG) for their ability to protect cortical neurons in culture from cell death induced by oxidative stress. This study reveals that none of the benzamide-based HDAC inhibitors (HDACIs) provides any neuroprotection whatsoever, in distinct contrast to HDACIs that contain other ZBGs. Some of the sulfur-contg. HDACIs, namely the thiols, thioesters, and disulfides present modest neuroprotective activity but show toxicity at higher concns. Taken together, these data demonstrate that the HDAC6-selective mercaptoacetamides that were reported previously provide the best protection in the homocysteic acid model of oxidative stress, thus further supporting their study in animal models of neurodegenerative diseases.
- 273He, R.; Chen, Y.; Chen, Y.; Ougolkov, A. V.; Zhang, J. S.; Savoy, D. N.; Billadeau, D. D.; Kozikowski, A. P. Synthesis and biological evaluation of triazol-4-ylphenyl-bearing histone deacetylase inhibitors as anticancer agents. J. Med. Chem. 2010, 53, 1347– 1356, DOI: 10.1021/jm901667k[ACS Full Text], [CAS], Google Scholar273https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXhvVGqug%253D%253D&md5=80c55a4aa2fd3cb5b440ff34aec02b7cSynthesis and Biological Evaluation of Triazol-4-ylphenyl-Bearing Histone Deacetylase Inhibitors as Anticancer AgentsHe, Rong; Chen, Yufeng; Chen, Yihua; Ougolkov, Andrei V.; Zhang, Jin-San; Savoy, Doris N.; Billadeau, Daniel D.; Kozikowski, Alan P.Journal of Medicinal Chemistry (2010), 53 (3), 1347-1356CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Our triazole-based histone deacetylase inhibitor (HDACI), octanedioic acid hydroxyamide[3-(1-phenyl-1H-[1,2,3]triazol-4-yl)phenyl]amide (4a), suppresses pancreatic cancer cell growth in vitro with the lowest IC50 value of 20 nM against MiaPaca-2 cell. In this study, we continued our efforts to develop triazol-4-ylphenyl bearing hydroxamate analogs by embellishing the terminal Ph ring of 4a with different substituents. The isoform inhibitory profile of these hydroxamate analogs was similar to those of 4a. All of these triazol-4-ylphenyl bearing hydroxamates are pan-HDACIs like SAHA. Moreover, compds. 4h (I) and 11a were found to be very effective inhibitors of cancer cell growth in the HupT3 (IC50 = 50 nM) and MiaPaca-2 (IC50 = 40 nM) cancer cell lines, resp. Compd. 4a was found to reactivate the expression of CDK inhibitor proteins and to suppress pancreatic cancer cell growth in vivo. Taken together, these data further support the value of the triazol-4-ylphenyl bearing hydroxamates in identifying potential pancreatic cancer therapies.
- 274Boissinot, M.; Inman, M.; Hempshall, A.; James, S. R.; Gill, J. H.; Selby, P.; Bowen, D. T.; Grigg, R.; Cockerill, P. N. Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192. Leuk. Res. 2012, 36, 1304– 1310, DOI: 10.1016/j.leukres.2012.07.002[Crossref], [PubMed], [CAS], Google Scholar274https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38XhtV2it7%252FJ&md5=3cd7587d757dcb74b99c10df0122dd63Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192Boissinot, Marjorie; Inman, Martyn; Hempshall, Aiden; James, Sally R.; Gill, Jason H.; Selby, Peter; Bowen, David T.; Grigg, Ronald; Cockerill, Peter N.Leukemia Research (2012), 36 (10), 1304-1310CODEN: LEREDD; ISSN:0145-2126. (Elsevier Ltd.)Histone deacetylase inhibitors (HDACIs) are in advanced clin. development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliph. compds. with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clin. trials, such as the benzamide group compds. MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compd. named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukemic origin. When tested in culture against the acute myeloid leukemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukemia.
- 275Suzuki, T.; Kasuya, Y.; Itoh, Y.; Ota, Y.; Zhan, P.; Asamitsu, K.; Nakagawa, H.; Okamoto, T.; Miyata, N. Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assembly. PLoS One 2013, 8, e68669 DOI: 10.1371/journal.pone.0068669[Crossref], [PubMed], [CAS], Google Scholar275https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXht1SgsrjF&md5=74d12c8fb1f06f8e00691415434fd929Identification of highly selective and potent histone deacetylase 3 inhibitors using click chemistry-based combinatorial fragment assemblySuzuki, Takayoshi; Kasuya, Yuki; Itoh, Yukihiro; Ota, Yosuke; Zhan, Peng; Asamitsu, Kaori; Nakagawa, Hidehiko; Okamoto, Takashi; Miyata, NaokiPLoS One (2013), 8 (7), e68669CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)To find histone deacetylase 3 (HDAC3)-selective inhibitors, a series of 504 candidates was assembled using "click chem.", by reacting nine alkynes bearing a zinc-binding group with 56 azide building blocks in the presence of Cu(I) catalyst. Screening of the 504-member triazole library against HDAC3 and other HDAC isoenzymes led to the identification of potent and selective HDAC3 inhibitors T247 and T326. These compds. showed potent HDAC3 inhibition with submicromolar IC50s, whereas they did not strongly inhibit other isoenzymes. Compds. T247 and T326 also induced a dose-dependent selective increase of NF-κB acetylation in human colon cancer HCT116 cells, indicating selective inhibition of HDAC3 in the cells. In addn., these HDAC3-selective inhibitors induced growth inhibition of cancer cells, and activated HIV gene expression in latent HIV-infected cells. These findings indicate that HDAC3-selective inhibitors are promising candidates for anticancer drugs and antiviral agents. This work also suggests the usefulness of the click chem. approach to find isoenzyme-selective HDAC inhibitors.
- 276Marson, C. M.; Matthews, C. J.; Yiannaki, E.; Atkinson, S. J.; Soden, P. E.; Shukla, L.; Lamadema, N.; Thomas, N. S. Discovery of potent, isoform-selective inhibitors of histone deacetylase containing chiral heterocyclic capping groups and a N-(2-aminophenyl)benzamide binding unit. J. Med. Chem. 2013, 56, 6156– 6174, DOI: 10.1021/jm400634n[ACS Full Text], [CAS], Google Scholar276https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhtVKitrfE&md5=afca61205f7bfeb7c33006df41e61737Discovery of Potent, Isoform-Selective Inhibitors of Histone Deacetylase Containing Chiral Heterocyclic Capping Groups and a N-(2-Aminophenyl)benzamide Binding UnitMarson, Charles M.; Matthews, Christopher J.; Yiannaki, Elena; Atkinson, Stephen J.; Soden, Peter E.; Shukla, Lena; Lamadema, Nermina; Thomas, N. Shaun B.Journal of Medicinal Chemistry (2013), 56 (15), 6156-6174CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The synthesis of a novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contain a heterocyclic capping group and a N-(2-aminophenyl)benzamide unit that binds in the active site. In vitro assays for the inhibition of HDAC1, HDAC2, HDAC3-NCoR1, and HDAC8 by the N-(2-aminophenyl)benzamide I gave resp. IC50 values of 930, 85, 12, and 4100 nM, exhibiting class I selectivity and potent inhibition of HDAC3-NCoR1. Both imidazolinone and thiazoline rings are shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)benzamides previously reported, an example of each ring system at 1 μM causing an increase in histone H3K9 acetylation in the human cell lines Jurkat and HeLa and an increase in cell death consistent with induction of apoptosis. Inhibition of the growth of MCF-7, A549, DU145, and HCT116 cell lines by I was obsd., with resp. IC50 values of 5.4, 5.8, 6.4, and 2.2 mM.
- 277Marson, C. M.; Matthews, C. J.; Atkinson, S. J.; Lamadema, N.; Thomas, N. S. Potent and selective inhibitors of histone deacetylase-3 containing chiral oxazoline capping groups and a N-(2-Aminophenyl)-benzamide binding unit. J. Med. Chem. 2015, 58, 6803– 6818, DOI: 10.1021/acs.jmedchem.5b00545[ACS Full Text], [CAS], Google Scholar277https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhtlOjur%252FO&md5=9a6fa3c009c84296988f194e1f958ee1Potent and Selective Inhibitors of Histone Deacetylase-3 Containing Chiral Oxazoline Capping Groups and a N-(2-Aminophenyl)-benzamide Binding UnitMarson, Charles M.; Matthews, Christopher J.; Atkinson, Stephen J.; Lamadema, Nermina; Thomas, N. Shaun B.Journal of Medicinal Chemistry (2015), 58 (17), 6803-6818CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A novel series of potent chiral inhibitors of histone deacetylase (HDAC) is described that contains an oxazoline capping group and a N-(2-aminophenyl)-benzamide unit. Among several new inhibitors of this type exhibiting Class I selectivity and potent inhibition of HDAC3-NCoR2, in vitro assays for the inhibition of HDAC1, HDAC2, and HDAC3-NCoR2 by N-(2-aminophenyl)-benzamide I gave resp. IC50 values of 80, 110, and 6 nM. Weak inhibition of all other HDAC isoforms (HDAC4, 5, 6, 7, and 9: IC50 > 100 000 nM; HDAC8: IC50 = 25 000 nM; HDAC10: IC50 > 4000 nM; HDAC11: IC50 > 2000 nM) confirmed the Class I selectivity of I. 2-Aminoimidazolinyl, 2-thioimidazolinyl, and 2-aminooxazolinyl units were shown to be effective replacements for the pyrimidine ring present in many other 2-(aminophenyl)-benzamides previously reported, but the 2-aminooxazolinyl unit was the most potent in inhibiting HDAC3-NCoR2. Many of the new HDAC inhibitors showed higher solubilities and lower binding to human serum albumin than that of Mocetinostat. Increases in histone H3K9 acetylation in the human cell lines U937 and PC-3 was obsd. for all three oxazolinyl inhibitors evaluated; those HDAC inhibitors also lowered cyclin E expression in U937 cells but not in PC-3 cells, indicating underlying differences in the mechanisms of action of the inhibitors on those two cell lines.
- 278Li, X.; Zhang, Y.; Jiang, Y.; Wu, J.; Inks, E. S.; Chou, C. J.; Gao, S.; Hou, J.; Ding, Q.; Li, J.; Wang, X.; Huang, Y.; Xu, W. Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study. Eur. J. Med. Chem. 2017, 134, 185– 206, DOI: 10.1016/j.ejmech.2017.03.069[Crossref], [PubMed], [CAS], Google Scholar278https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvFWnt70%253D&md5=66ad0ddda5b3e46ef07dfb40951b63dbSelective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity studyLi, Xiaoyang; Zhang, Yingjie; Jiang, Yuqi; Wu, Jingde; Inks, Elizabeth S.; Chou, C. James; Gao, Shuai; Hou, Jinning; Ding, Qinge; Li, Jingyao; Wang, Xue; Huang, Yongxue; Xu, WenfangEuropean Journal of Medicinal Chemistry (2017), 134 (), 185-206CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compd. 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compds. exhibited high HDACs inhibitory potency. Compd. 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In vivo studies revealed that compd. 11a displayed potent oral antitumor activity in both hematol. tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and Ph compds. (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine contg. compd. 56, with moderate HDAC3 selectivity.
- 279Hsieh, H. Y.; Chuang, H. C.; Shen, F. H.; Detroja, K.; Hsin, L. W.; Chen, C. S. Targeting breast cancer stem cells by novel HDAC3-selective inhibitors. Eur. J. Med. Chem. 2017, 140, 42– 51, DOI: 10.1016/j.ejmech.2017.08.069[Crossref], [PubMed], [CAS], Google Scholar279https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhsFWnsbnL&md5=a0ad5d8e018d7471975602be2ba238ebTargeting breast cancer stem cells by novel HDAC3-selective inhibitorsHsieh, Hao-Yu; Chuang, Hsiao-Ching; Shen, Fang-Hsiu; Detroja, Kinjal; Hsin, Ling-Wei; Chen, Ching-ShihEuropean Journal of Medicinal Chemistry (2017), 140 (), 42-51CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-neg. breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivs. exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the down regulation of β-catenin.
- 280McClure, J. J.; Inks, E. S.; Zhang, C.; Peterson, Y. K.; Li, J.; Chundru, K.; Lee, B.; Buchanan, A.; Miao, S.; Chou, C. J. Comparison of the deacylase and deacetylase activity of zinc-dependent HDACs. ACS Chem. Biol. 2017, 12, 1644– 1655, DOI: 10.1021/acschembio.7b00321[ACS Full Text], [CAS], Google Scholar280https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXmvVent7w%253D&md5=7e6a761d303149a0367afbbe5a019d80Comparison of the deacylase and deacetylase activity of zinc-dependent HDACsMcClure, Jesse J.; Inks, Elizabeth S.; Zhang, Cheng; Peterson, Yuri K.; Li, Jiaying; Chundru, Kalyan; Lee, Bradley; Buchanan, Ashley; Miao, Shiqin; Chou, C. JamesACS Chemical Biology (2017), 12 (6), 1644-1655CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)The acetylation status of lysine residues on histone proteins has long been attributed to a balance struck between the catalytic activity of histone acetyl transferases and histone deacetylases (HDAC). HDACs were identified as the sole removers of acetyl post-translational modifications (PTM) of histone lysine residues. Studies into the biol. role of HDACs have also elucidated their role as removers of acetyl PTMs from lysine residues of nonhistone proteins. These findings, coupled with high-resoln. mass spectrometry studies that revealed the presence of acyl-group PTMs on lysine residues of nonhistone proteins, brought forth the possibility of HDACs acting as removers of both acyl- and acetyl-based PTMs. We posited that HDACs fulfill this dual role and sought to investigate their specificity. Utilizing a fluorescence-based assay and biol. relevant acyl-substrates, the selectivities of zinc-dependent HDACs toward these acyl-based PTMs were identified. These findings were further validated using cellular models and mol. biol. techniques. As a proof of principal, an HDAC3 selective inhibitor was designed using HDAC3's substrate preference. This resulting inhibitor demonstrates nanomolar activity and >30 fold selectivity toward HDAC3 compared to the other class I HDACs. This inhibitor is capable of increasing p65 acetylation, attenuating NF-κB activation, and thereby preventing downstream nitric oxide signaling. Addnl., this selective HDAC3 inhibition allows for control of HMGB-1 secretion from activated macrophages without altering the acetylation status of histones or tubulin.
- 281Ocasio, C. A.; Sansook, S.; Jones, R.; Roberts, J. M.; Scott, T. G.; Tsoureas, N.; Coxhead, P.; Guille, M.; Tizzard, G. J.; Coles, S. J.; Hochegger, H.; Bradner, J. E.; Spencer, J. Pojamide: An HDAC3-selective ferrocene analogue with remarkably enhanced redox-triggered ferrocenium activity in cells. Organometallics 2017, 36, 3276– 3283, DOI: 10.1021/acs.organomet.7b00437[ACS Full Text], [CAS], Google Scholar281https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhtlGhtr%252FM&md5=ce4c27bec86738e1c618c9eb5c8cba70Pojamide: An HDAC3-Selective Ferrocene Analogue with Remarkably Enhanced Redox-Triggered Ferrocenium Activity in CellsOcasio, Cory A.; Sansook, Supojjanee; Jones, Rhiannon; Roberts, Justin M.; Scott, Thomas G.; Tsoureas, Nikolaos; Coxhead, Peter; Guille, Matthew; Tizzard, Graham J.; Coles, Simon J.; Hochegger, Helfrid; Bradner, James E.; Spencer, JohnOrganometallics (2017), 36 (17), 3276-3283CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)A ferrocene contg. ortho-aminoanilide, N1-(2-aminophenyl)-N8-ferrocenyloctanediamide, 2b (Pojamide) displayed nanomolar potency vs. HDAC3. Compared to RGFP966, a potent and selective HDAC3 inhibitor, Pojamide displayed superior activity in HCT116 colorectal cancer cell invasion assays; however, TCH106 and Romidepsin, potent HDAC1 inhibitors, outperformed Pojamide in cellular proliferation and colony formation assays. Together, these data suggest that HDAC 1 and 3 inhibition is desirable to achieve max. anticancer benefits. Addnl., the authors explored Pojamide-induced redox-pharmacol. Indeed, treating HCT116 cells with Pojamide, SNP (Na nitroprusside) and glutathione (GSH) led to greatly enhanced cytotoxicity and DNA damage attributed to activation to an Fe(III) species.
- 282Trivedi, P.; Adhikari, N.; Amin, S. A.; Jha, T.; Ghosh, B. Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects. Eur. J. Pharm. Sci. 2018, 124, 165– 181, DOI: 10.1016/j.ejps.2018.08.030[Crossref], [PubMed], [CAS], Google Scholar282https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1emtr7L&md5=b0e2696ed9abb37d574b22b1be36da90Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effectsTrivedi, Prakruti; Adhikari, Nilanjan; Amin, Sk. Abdul; Jha, Tarun; Ghosh, BalaramEuropean Journal of Pharmaceutical Sciences (2018), 124 (), 165-181CODEN: EPSCED; ISSN:0928-0987. (Elsevier B.V.)Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A no. of HDAC inhibitors have been used pre-clin. and clin. as anticancer agents. In the current study, we have designed and synthesized compd. 12a by combining the scaffolds of CI-994 and BG45. Moreover, the structure of compd. 12a was optimized and a series of 2-aminobenzamide derivs. were synthesized further. These compds. were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compd. 26c showed 11.68-fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compds. exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compd. 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI-994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small mol. HDAC3 inhibitors to fight against the target specific malignancies in future.
- 283Cao, F.; de Weerd, S.; Chen, D.; Zwinderman, M. R. H.; van der Wouden, P. E.; Dekker, F. J. Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC). Eur. J. Med. Chem. 2020, 208, 112800, DOI: 10.1016/j.ejmech.2020.112800[Crossref], [PubMed], [CAS], Google Scholar283https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhvFSisbrI&md5=8e9bb1f170b924f07ef4186e9f6fdac4Induced protein degradation of histone deacetylases 3 (HDAC3) by proteolysis targeting chimera (PROTAC)Cao, Fangyuan; de Weerd, Sander; Chen, Deng; Zwinderman, Martijn R. H.; van der Wouden, Petra E.; Dekker, Frank J.European Journal of Medicinal Chemistry (2020), 208 (), 112800CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Histone deacetylases (HDACs) play important roles in inflammatory diseases like asthma and chronic obstructive pulmonary disease (COPD). Unravelling of and interfering with the functions of specific isoenzymes contributing to inflammation provides opportunities for drug development. Here we synthesize proteolysis targeting chimeras (PROTACs) for degrdn. of class I HDACs in which o-aminoanilide-based class I HDAC inhibitors are tethered to the cereblon ligand pomalidomide. One of these PROTACs, denoted HD-TAC7, showed promising degrdn. effects for HDAC3 with a DC50 value of 0.32 μM. In contrast to biochem. evidence using siRNA, HD-TAC7 showed a minimal effect on gene expression in LPS/IFNγ-stimulated RAW 264.7 macrophages. The lack of effect can be attributed to downregulation of the NF-κB subunit p65, which is a known side effect of pomalidomide treatment. Altogether, we describe a novel PROTAC that enables selective downregulation of HDAC3 levels, however we note that concomitant downregulation of the NF-κB subunit p65 can confound the biol. outcome.
- 284McClure, J. J.; Zhang, C.; Inks, E. S.; Peterson, Y. K.; Li, J.; Chou, C. J. Development of allosteric hydrazide-containing Class I histone deacetylase inhibitors for use in acute myeloid leukemia. J. Med. Chem. 2016, 59, 9942– 9959, DOI: 10.1021/acs.jmedchem.6b01385[ACS Full Text], [CAS], Google Scholar284https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC28Xhs12gtbrE&md5=52d5222010a0de3cfecde9a04c3efb84Development of Allosteric Hydrazide-Containing Class I Histone Deacetylase Inhibitors for Use in Acute Myeloid LeukemiaMcClure, Jesse J.; Zhang, Cheng; Inks, Elizabeth S.; Peterson, Yuri K.; Li, Jiaying; Chou, C. JamesJournal of Medicinal Chemistry (2016), 59 (21), 9942-9959CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compds. contg. this motif require much higher dosing in clinic to achieve therapeutic concns. With the goal of developing a second generation of HDAC inhibitors, lacking this hydroxamate, the authors designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of the authors' lead analogs' efficacy, selectivity, and toxicity profiles demonstrate they possess low nanomolar activity against models of Acute Myeloid Leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells.
- 285Li, X.; Peterson, Y. K.; Inks, E. S.; Himes, R. A.; Li, J.; Zhang, Y.; Kong, X.; Chou, C. J. Class I HDAC inhibitors display different antitumor mechanism in leukemia and prostatic cancer cells depending on their p53 status. J. Med. Chem. 2018, 61, 2589– 2606, DOI: 10.1021/acs.jmedchem.8b00136[ACS Full Text], [CAS], Google Scholar285https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXjslKrs7w%253D&md5=36fcd594770688e5dcbbdbd3c8619b89Class I HDAC Inhibitors Display Different Antitumor Mechanism in Leukemia and Prostatic Cancer Cells Depending on Their p53 StatusLi, Xiaoyang; Peterson, Yuri K.; Inks, Elizabeth S.; Himes, Richard A.; Li, Jiaying; Zhang, Yingjie; Kong, Xiujie; Chou, C. JamesJournal of Medicinal Chemistry (2018), 61 (6), 2589-2603CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Previously, we designed and synthesized a series of o-aminobenzamide-based histone deacetylase (HDAC) inhibitors, among which the representative compd. I exhibited potent inhibitory activity against class I HDACs. In this study, we report the development of more potent hydrazide-based class I selective HDAC inhibitors using II as a lead. Representative compd. 13b showed a mixed, slow, and tight binding inhibition mechanism for HDAC1, 2, and 3. The most potent compd. 13e exhibited low nanomolar IC50s toward HDAC1, 2, and 3 and could down-regulate HDAC6 in acute myeloid leukemia MV4-11 cells. The EC50 of 13e against MV4-11 cells was 34.7 nM, which is 26 times lower than its parent compd. 11a. In vitro responses to 13e vary significantly and interestingly based on cell type: in p53 wild-type MV4-11 cells, 13e induced cell death via apoptosis and G1/S cell cycle arrest, which is likely mediated by a p53-dependent pathway, while in p53-null PC-3 cells, 13e caused G2/M arrest and inhibited cell proliferation without inducing caspase-3-dependent apoptosis.
- 286Li, X.; Jiang, Y.; Peterson, Y. K.; Xu, T.; Himes, R. A.; Luo, X.; Yin, G.; Inks, E. S.; Dolloff, N.; Halene, S.; Chan, S. S. L.; Chou, C. J. Design of hydrazide-bearing HDACIs based on panobinostat and their p53 and FLT3-ITD dependency in antileukemia activity. J. Med. Chem. 2020, 63, 5501– 5525, DOI: 10.1021/acs.jmedchem.0c00442[ACS Full Text], [CAS], Google Scholar286https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXnslShs7w%253D&md5=6be6aca92100a8e8ed437275c87f22c0Design of Hydrazide-Bearing HDACIs Based on Panobinostat and Their p53 and FLT3-ITD Dependency in Antileukemia ActivityLi, Xiaoyang; Jiang, Yuqi; Peterson, Yuri K.; Xu, Tongqiang; Himes, Richard A.; Luo, Xin; Yin, Guilin; Inks, Elizabeth S.; Dolloff, Nathan; Halene, Stephanie; Chan, Sherine S. L.; Chou, C. JamesJournal of Medicinal Chemistry (2020), 63 (10), 5501-5525CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)Here, we present a new series of hydrazide-bearing class I selective HDAC inhibitors designed based on panobinostat. The cap, linker, and zinc-binding group were derivatized to improve HDAC affinity and antileukemia efficacy. Lead inhibitor 13a shows picomolar or low nanomolar IC50 values against HDAC1 and HDAC3 and exhibits differential toxicity profiles toward multiple cancer cells with different FLT3 and p53 statuses. 13a indirectly inhibits the FLT3 signaling pathway and down-regulates master antiapoptotic proteins, resulting in the activation of pro-caspase3 in wt-p53 FLT3-ITD MV4-11 cells. While in the wt-FLT3 and p53-null cells, 13a(I) is incapable of causing apoptosis at a therapeutic concn. The MDM2 antagonist and the proteasome inhibitor promote 13a-triggered apoptosis by preventing p53 degrdn. Furthermore, we demonstrate that apoptosis rather than autophagy is the key contributing factor for 13a-triggered cell death. When compared to panobinostat, 13a is not mutagenic and displays superior in vivo bioavailability and a higher AUC0-inf value.
- 287Xiao, Y.; Wang, J.; Zhao, L. Y.; Chen, X.; Zheng, G.; Zhang, X.; Liao, D. Discovery of histone deacetylase 3 (HDAC3)-specific PROTACs. Chem. Commun. 2020, 56, 9866– 9869, DOI: 10.1039/D0CC03243C[Crossref], [PubMed], [CAS], Google Scholar287https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhsVaqurvL&md5=828f9a26ff7c3e7f8736d0c9fdd0a3beDiscovery of histone deacetylase 3 (HDAC3)-specific PROTACsXiao, Yufeng; Wang, Jia; Zhao, Lisa Y.; Chen, Xinyi; Zheng, Guangrong; Zhang, Xuan; Liao, DaiqingChemical Communications (Cambridge, United Kingdom) (2020), 56 (68), 9866-9869CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)Histone deacetylases (HDACs) are validated drug targets for cancer treatment. Increased HDAC isoenzyme selectivity and novel strategies to inhibit HDAC activity could lead to safer and more effective drug candidates. Nonetheless, it is quite challenging to develop isoenzyme-specific HDACi due to the highly conserved catalytic domain. We discovered XZ9002, a first-in-class HDAC3-specific PROTAC that potently degraded HDAC3. Importantly, XZ9002 is more effective to inhibit cancer cell proliferation than its proteolysis-inactive counterpart, suggesting HDAC3 degrdn. is a novel and promising anticancer approach.
- 288Liu, J.; Yu, Y.; Kelly, J.; Sha, D.; Alhassan, A. B.; Yu, W.; Maletic, M. M.; Duffy, J. L.; Klein, D. J.; Holloway, M. K.; Carroll, S.; Howell, B. J.; Barnard, R. J. O.; Wolkenberg, S.; Kozlowski, J. A. Discovery of highly selective and potent HDAC3 inhibitors based on a 2-substituted benzamide zinc binding group. ACS Med. Chem. Lett. 2020, 11, 2476– 2483, DOI: 10.1021/acsmedchemlett.0c00462[ACS Full Text], [CAS], Google Scholar288https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXitVeqsrrN&md5=fd3c45a5941acbc7876ac51e799b66acDiscovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding GroupLiu, Jian; Yu, Younong; Kelly, Joseph; Sha, Deyou; Alhassan, Abdul-Basit; Yu, Wensheng; Maletic, Milana M.; Duffy, Joseph L.; Klein, Daniel J.; Holloway, M. Katharine; Carroll, Steve; Howell, Bonnie J.; Barnard, Richard J. O.; Wolkenberg, Scott; Kozlowski, Joseph A.ACS Medicinal Chemistry Letters (2020), 11 (12), 2476-2483CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chem. (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series contg. 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compd. 16 with a 2-methylthiobenzamide. Compd. 16 inhibited HDAC3 with an IC50 of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in 20 retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis 16 and 20 bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compds. for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.
- 289Kinzel, O.; Llauger-Bufi, L.; Pescatore, G.; Rowley, M.; Schultz-Fademrecht, C.; Monteagudo, E.; Fonsi, M.; Gonzalez Paz, O.; Fiore, F.; Steinkühler, C.; Jones, P. Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties. J. Med. Chem. 2009, 52, 3453– 3456, DOI: 10.1021/jm9004303[ACS Full Text], [CAS], Google Scholar289https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXlvFWnsb0%253D&md5=8674adc0c3892942a1fc7b154cbc84b4Discovery of a Potent Class I Selective Ketone Histone Deacetylase Inhibitor with Antitumor Activity in Vivo and Optimized Pharmacokinetic PropertiesKinzel, Olaf; Llauger-Bufi, Laura; Pescatore, Giovanna; Rowley, Michael; Schultz-Fademrecht, Carsten; Monteagudo, Edith; Fonsi, Massimiliano; Gonzalez Paz, Odalys; Fiore, Fabrizio; Steinkuhler, Christian; Jones, PhilipJournal of Medicinal Chemistry (2009), 52 (11), 3453-3456CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclin. species, has a clean off-target profile, and is neg. in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.
- 290Hamoud, M. M. S.; Pulya, S.; Osman, N. A.; Bobde, Y.; Hassan, A. E. A.; Abdel-Fattah, H. A.; Ghosh, B.; Ghanim, A. M. Design, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitors. New J. Chem. 2020, 44, 9671– 9683, DOI: 10.1039/D0NJ01274B[Crossref], [CAS], Google Scholar290https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BB3cXhtFGlsLfF&md5=d532ffd3c380e25543df325f12bdba3aDesign, synthesis, and biological evaluation of novel nicotinamide derivatives as potential histone deacetylase-3 inhibitorsHamoud, Mohamed M. S.; Pulya, Sravani; Osman, Nermine A.; Bobde, Yamini; Hassan, Abdalla E. A.; Abdel-Fattah, Hanan A.; Ghosh, Balaram; Ghanim, Amany M.New Journal of Chemistry (2020), 44 (23), 9671-9683CODEN: NJCHE5; ISSN:1144-0546. (Royal Society of Chemistry)Most of the FDA approved histone deacetylase inhibitors (HDACi) contain hydroxamate as the zinc binding group (ZBG). Hydroxamates form strong electrostatic metal chelation with divalent zinc present in HDAC. This strong zinc chelation leads to unwanted metabolic abnormalities. Therefore, the design of a non-hydroxamate moiety as a ZBG encourages medicinal chem. researchers. Here, a series of nicotinamide derivs. have been designed and synthesized as HDACi. All compds. were tested for their inhibitory activities against pan HDACs (contg. predominantly HDAC1 and HDAC2 isoenzymes) and against the HDAC3 isoform. Among these, compds. 6b and 6n showed comparable pan HDAC inhibitory activity (IC50 = 4.648 μM and IC50 = 5.481 μM, resp.) compared with BG45 (IC50 = 5.506 μM). Compd. 6b exhibited the best potency against HDAC3 with IC50 = 0.694 μM. In addn., the anti-proliferative activity of the synthesized compds. 6a-s was evaluated against three different cancer cell lines including B16F10, MCF-7, and A549. Compd. 6b(I) displayed the highest anti-proliferative potency (IC50 = 4.66 μM in B16F10 cell lines) and compds. 6b, 6c, 6h, 6i, 6l, 6m, and 6n exhibited higher cytotoxicity against all cell lines compared with the ref. BG45. The selected potent compds. also displayed significant selectivity against cancer cell lines over normal human embryonic kidney (HEK-293) cell lines. The mol. modeling study displayed possible interactions between the most potent inhibitor 6b and HDAC3 active sites. Furthermore, the predicted in silico studies of all target compds. revealed acceptable physicochem. properties and pharmacokinetic parameters.
- 291Wang, C.; Henkes, L. M.; Doughty, L. B.; He, M.; Wang, D.; Meyer-Almes, F. J.; Cheng, Y. Q. Thailandepsins: bacterial products with potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities. J. Nat. Prod. 2011, 74, 2031– 2038, DOI: 10.1021/np200324x[ACS Full Text], [CAS], Google Scholar291https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3MXpsFSlu7g%253D&md5=1fc01e68dd5021a37931ed1c297f8570Thailandepsins: Bacterial Products with Potent Histone Deacetylase Inhibitory Activities and Broad-Spectrum Antiproliferative ActivitiesWang, Cheng; Henkes, Leonhard M.; Doughty, Leah B.; He, Min; Wang, Di-Fei; Meyer-Almes, Franz-Josef; Cheng, Yi-QiangJournal of Natural Products (2011), 74 (10), 2031-2038CODEN: JNPRDF; ISSN:0163-3864. (American Chemical Society-American Society of Pharmacognosy)Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer drugs, with one synthetic compd., SAHA (vorinostat, Zolinza), and one natural product, FK228 (depsipeptide, romidepsin, Istodax), approved by FDA for clin. use. The authors' studies of FK228 biosynthesis in Chromobacterium violaceum no. 968 led to the identification of a cryptic biosynthetic gene cluster in the genome of Burkholderia thailandensis E264. Genome mining and genetic manipulation of this gene cluster further led to the discovery of two new products, thailandepsin A and thailandepsin B. HDAC inhibition assays showed that thailandepsins have selective inhibition profiles different from that of FK228, with comparable inhibitory activities to those of FK228 toward human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9 but weaker inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which could be beneficial. NCI-60 anticancer screening assays showed that thailandepsins possess broad-spectrum antiproliferative activities with GIC50 for over 90% of the tested cell lines at low nanomolar concns. and potent cytotoxic activities toward certain types of cell lines, particularly for those derived from colon, melanoma, ovarian, and renal cancers. Thailandepsins thus represent new naturally produced HDAC inhibitors that are promising for anticancer drug development.
- 292Li, X.; Tu, Z.; Li, H.; Liu, C.; Li, Z.; Sun, Q.; Yao, Y.; Liu, J.; Jiang, S. Biological evaluation of new largazole analogues: alteration of macrocyclic scaffold with click chemistry. ACS Med. Chem. Lett. 2013, 4, 132– 136, DOI: 10.1021/ml300371t[ACS Full Text], [CAS], Google Scholar292https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC38Xhsl2mu7zF&md5=58d90326cc3eafe8d68e99d6a2801b8cBiological evaluation of new largazole analogues: Alteration of macrocyclic scaffold with Click chemistryLi, Xianlin; Tu, Zhenchao; Li, Hua; Liu, Chunping; Li, Zheng; Sun, Qiao; Yao, Yiwu; Liu, Jinsong; Jiang, ShengACS Medicinal Chemistry Letters (2013), 4 (1), 132-136CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)We report the design, synthesis, and biol. evaluation of a new series of largazole analogs in which a 4-methylthiazoline moiety was replaced with a triazole and tetrazole ring, resp. Compd. (I) bearing a tetrazole ring was identified to show much better selectivity for HDAC1 over HDAC9 than largazole (10-fold). This work could serve as a foundation for further exploration of selective HDAC inhibitors using a largazole mol. scaffold.
- 293Taori, K.; Paul, V. J.; Luesch, H. Structure and activity of largazole, a potent antiproliferative agent from the Floridian marine cyanobacterium Symploca sp. J. Am. Chem. Soc. 2008, 130, 1806– 1807, DOI: 10.1021/ja7110064[ACS Full Text], [CAS], Google Scholar293https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotFGhtw%253D%253D&md5=bcd18bbee431e273c1b646f3c9c1388bStructure and Activity of Largazole, a Potent Antiproliferative Agent from the Floridian Marine Cyanobacterium Symploca sp.Taori, Kanchan; Paul, Valerie J.; Luesch, HendrikJournal of the American Chemical Society (2008), 130 (6), 1806-1807CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)A novel cytotoxic cyclodepsipeptide, termed largazole, has been isolated from the marine cyanobacterium Symploca sp. collected in the Florida Keys. Its planar structure was elucidated by 1D and 2D NMR spectroscopy in conjunction with mass spectrometry. The abs. configuration of largazole was detd. by chem. degrdn. followed by chiral HPLC anal. Largazole possesses densely assembled unusual structural features, including a rare 4-methylthiazoline linearly fused to a thiazole in its cyclic core and a hitherto undescribed 3-hydroxy-7-mercaptohept-4-enoic acid unit incorporated in an ester, thioester, and amide framework. Largazole exhibits potent antiproliferative activity and preferentially targets cancer cells over nontransformed cells.
- 294Bowers, A.; West, N.; Taunton, J.; Schreiber, S. L.; Bradner, J. E.; Williams, R. M. Total synthesis and biological mode of action of largazole: a potent class I histone deacetylase inhibitor. J. Am. Chem. Soc. 2008, 130, 11219– 11222, DOI: 10.1021/ja8033763[ACS Full Text], [CAS], Google Scholar294https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXos12ru78%253D&md5=0063841a5d6a996484cdb329ff6baa64Total synthesis and biological mode of action of largazole: A potent Class I histone deacetylase inhibitorBowers, Albert; West, Nathan; Taunton, Jack; Schreiber, Stuart L.; Bradner, James E.; Williams, Robert M.Journal of the American Chemical Society (2008), 130 (33), 11219-11222CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)The efficient total synthesis of the recently described natural substance largazole and its active metabolite largazole thiol is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-rug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite largazole thiol, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and largazole thiol have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances.
- 295Ying, Y.; Taori, K.; Kim, H.; Hong, J.; Luesch, H. Total synthesis and molecular target of largazole, a histone deacetylase inhibitor. J. Am. Chem. Soc. 2008, 130, 8455– 8459, DOI: 10.1021/ja8013727[ACS Full Text], [CAS], Google Scholar295https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXmsVeksr4%253D&md5=d580c55dfc1c921346a8d79b2b96baa3Total Synthesis and Molecular Target of Largazole, a Histone Deacetylase InhibitorYing, Yongcheng; Taori, Kanchan; Kim, Hyoungsu; Hong, Jiyong; Luesch, HendrikJournal of the American Chemical Society (2008), 130 (26), 8455-8459CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)Full details of the concise and convergent synthesis (eight steps, 19% overall yield), its extension to the prepn. of a series of key analogs, and the mol. target and pharmacophore of largazole are described. Central to the synthesis of largazole is a macrocyclization reaction for formation of the strained 16-membered depsipeptide core followed by an olefin cross-metathesis reaction for installation of the thioester. The biol. evaluation of largazole and its key analogs, including an acetyl analog, a thiol analog, and a hydroxyl analog, suggested that histone deacetylases (HDACs) are mol. targets of largazole and largazole is a class I HDAC inhibitor. In addn., structure-activity relationship (SAR) studies revealed that the thiol group is the pharmacophore of the natural product. Largazole's HDAC inhibitory activity correlates with its antiproliferative activity.
- 296Seiser, T.; Kamena, F.; Cramer, N. Synthesis and biological activity of largazole and derivatives. Angew. Chem., Int. Ed. 2008, 47, 6483– 6485, DOI: 10.1002/anie.200802043[Crossref], [CAS], Google Scholar296https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtVCksbrN&md5=e92870aac334b2051b87cf75e67efffeSynthesis and biological activity of largazole and derivativesSeiser, Tobias; Kamena, Faustin; Cramer, NicolaiAngewandte Chemie, International Edition (2008), 47 (34), 6483-6485CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)A modular synthesis of the marine natural product largazole and related synthetic analogs is described. Largazole was prepd. in 10% overall yield through a synthetic route with a longest linear sequence of nine steps. Activity tests showed the necessity of the thiobutenyl moiety for antiproliferative activity.
- 297Ghosh, A. K.; Kulkarni, S. Enantioselective total synthesis of (+)-largazole, a potent inhibitor of histone deacetylase. Org. Lett. 2008, 10, 3907– 3909, DOI: 10.1021/ol8014623[ACS Full Text], [CAS], Google Scholar297https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVGjtbk%253D&md5=5e471389e15c2f0e207727bb9e9038a2Enantioselective Total Synthesis of (+)-Largazole, a Potent Inhibitor of Histone DeacetylaseGhosh, Arun K.; Kulkarni, SarangOrganic Letters (2008), 10 (17), 3907-3909CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)An enantioselective total synthesis of the cytotoxic natural product (+)-largazole (I) is described. It is a potent histone deacetylase inhibitor. The synthesis is convergent and involves the coupling of the free carboxylic acid, derived from thiazole ester II, with Boc-amino ester III, followed by cycloamidation of the corresponding amino acid. The synthesis features an efficient cross-metathesis, an enzymic kinetic resoln. of a β-hydroxy ester, a selective removal of a Boc-protecting group, a HATU/HOAt-promoted cycloamidation reaction, and synthetic manipulations to a sensitive thioester functional group.
- 298Nasveschuk, C. G.; Ungermannova, D.; Liu, X.; Phillips, A. J. A concise total synthesis of largazole, solution structure, and some preliminary structure activity relationships. Org. Lett. 2008, 10, 3595– 3598, DOI: 10.1021/ol8013478[ACS Full Text], [CAS], Google Scholar298https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXotlOmurs%253D&md5=404766f9f4fce793550504328f11f43cA Concise Total Synthesis of Largazole, Solution Structure, and Some Preliminary Structure Activity RelationshipsNasveschuk, Christopher G.; Ungermannova, Dana; Liu, Xuedong; Phillips, Andrew J.Organic Letters (2008), 10 (16), 3595-3598CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)A total synthesis of largazole (I) that proceeds in 8 steps from com. materials is reported, along with some structure-activity relationships. A combination of NMR studies and mol. modeling have also provided a preliminary picture of the conformation of largazole.
- 299Terracciano, S.; Di Micco, S.; Bifulco, G.; Gallinari, P.; Riccio, R.; Bruno, I. Synthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222. Bioorg. Med. Chem. 2010, 18, 3252– 3260, DOI: 10.1016/j.bmc.2010.03.022[Crossref], [PubMed], [CAS], Google Scholar299https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3cXlsFCkurY%253D&md5=fb504ea753abff24d7d9e825f881988eSynthesis and biological activity of cyclotetrapeptide analogues of the natural HDAC inhibitor FR235222Terracciano, Stefania; Di Micco, Simone; Bifulco, Giuseppe; Gallinari, Paola; Riccio, Raffaele; Bruno, InesBioorganic & Medicinal Chemistry (2010), 18 (9), 3252-3260CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)In the course of their ongoing efforts to discover new and more effective HDAC inhibitors for the development of anticancer agents, the authors have recently undertaken a mol. modeling study on a small collection of FR235222 analogs, synthesized in the frame of a structure-activity relationship investigation, made in order to identify the key structural elements essential for the activity. Progress made in structure elucidation of HDAC active site, together with accurate docking calcns., provided new structural insights useful for a further refinement of the tetrapeptide scaffold, which should assure an optimal interaction between the synthetic ligands and the biol. target. Using computer-based modeling methods, the authors synthesized six new cyclotetrapeptide analogs (3-8) of FR235222, bearing a carboxylic or an hydroxamic acid functionality as Zn binding moiety. Herein, the authors describe the synthesis and inhibition activity of cyclotetrapeptides on different HDAC isoforms.
- 300Zhang, Y.; Yang, P.; Chou, C. J.; Liu, C.; Wang, X.; Xu, W. Development of N-Hydroxycinnamamide-based histone deacetylase inhibitors with indole-containing cap group. ACS Med. Chem. Lett. 2013, 4, 235– 238, DOI: 10.1021/ml300366t[ACS Full Text], [CAS], Google Scholar300https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXkt12hsQ%253D%253D&md5=36a817a03f74290769cb0dcbbb7c5ce0Development of N-Hydroxycinnamamide-Based Histone Deacetylase Inhibitors with an Indole-Containing Cap GroupZhang, Yingjie; Yang, Penghui; Chou, C. James; Liu, Chunxi; Wang, Xuejian; Xu, WenfangACS Medicinal Chemistry Letters (2013), 4 (2), 235-238CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)A novel series of histone deacetylase inhibitors combining N-hydroxycinnamamide bioactive fragment and indole bioactive fragment was designed and synthesized. Several compds. exhibited comparable, even superior, total HDACs inhibitory activity and in vitro antiproliferative activities relative to the approved drug SAHA. A representative compd. I with moderate HDACs inhibition was progressed to isoform selectivity profile, Western blot anal., and in vivo antitumor assay. Although HDACs isoform selectivity of I was similar to that of SAHA, the Western blot results indicated that intracellular effects of I at 1 μM were class I selective. It was noteworthy that the effect on histone H4 acetylation of SAHA decreased with time, while the effect on histone H4 acetylation of I was maintained and even increased. Most importantly, compd. I exhibited promising in vivo antitumor activity in a U937 xenograft model.
- 301Zhang, L.; Zhang, Y.; Chou, C. J.; Inks, E. S.; Wang, X.; Li, X.; Hou, J.; Xu, W. Histone deacetylase inhibitors with enhanced enzymatic inhibition effects and potent in vitro and in vivo antitumor activities. ChemMedChem 2014, 9, 638– 648, DOI: 10.1002/cmdc.201300297[Crossref], [PubMed], [CAS], Google Scholar301https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC3sXhslGntbnM&md5=a9575d05eeef6ea997a0b435176779ddHistone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Antitumor ActivitiesZhang, Lei; Zhang, Yingjie; Chou, C. James; Inks, Elizabeth S.; Wang, Xuejian; Li, Xiaoguang; Hou, Jinning; Xu, WenfangChemMedChem (2014), 9 (3), 638-648CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)A series of small mols. I (R = 4-ClC6H4CO, 1-naphthylsulfonyl, 2-MeOC6H4NHCO, etc.) was designed and synthesized based on structural optimization. A significant improvement in the enzyme inhibitory activity of these compds. was discovered. Moreover, the tested compds. have moderate preference for class I HDACs over HDAC6, as demonstrated by enzyme selectivity assays. In vitro antiproliferation assay results showed that representative compds. can selectively inhibit the growth of non-solid lymphoma and leukemic cells such as U937, K562, and HL60. In the in vivo antitumor assay, I (R = 5-dimethylamino-1-naphthylsulfonyl) showed better performance than SAHA in blocking U937 tumor growth. Western blot anal. revealed that representative mols. can block the function of both class I HDACs and HDAC6. More importantly, the western blot results revealed that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by these compds. in the U937 cell line rather than MDA-MB-231 cells. This distinction in cellular mechanism might be an important reason why the U937 cell line was found to more sensitive to our HDAC inhibitors than the MDA-MB-231 cell line.
- 302Abdelkarim, H.; Neelarapu, R.; Madriaga, A.; Vaidya, A. S.; Kastrati, I.; Karumudi, B.; Wang, Y. T.; Taha, T. Y.; Thatcher, G. R. J.; Frasor, J.; Petukhov, P. A. Design, synthesis, molecular modeling, and biological evaluation of novel amine-based histone deacetylase inhibitors. ChemMedChem 2017, 12, 2030– 2043, DOI: 10.1002/cmdc.201700449[Crossref], [PubMed], [CAS], Google Scholar302https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXhvV2nsbvL&md5=fcb3babf90d0048e4806e7faaf3e674cDesign, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Amine-based Histone Deacetylase InhibitorsAbdelkarim, Hazem; Neelarapu, Raghupathi; Madriaga, Antonett; Vaidya, Aditya S.; Kastrati, Irida; Karumudi, Bhargava; Wang, Yue-ting; Taha, Taha Y.; Thatcher, Gregory R. J.; Frasor, Jonna; Petukhov, Pavel A.ChemMedChem (2017), 12 (24), 2030-2043CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)Histone deacetylases (HDACs) are promising drug targets for a variety of therapeutic applications. Herein we describe the design, synthesis, biol. evaluation in cellular models of cancer, and preliminary drug metab. and pharmacokinetic studies (DMPK) of a series of secondary and tertiary N-substituted 7-aminoheptanohydroxamic acid-based HDAC inhibitors. Introduction of an amino group with one or two surface binding groups (SBGs) yielded a successful strategy to develop novel and potent HDAC inhibitors. The secondary amines were found to be generally more potent than the corresponding tertiary amines. Docking studies suggested that the SBGs of tertiary amines cannot be favorably accommodated at the gorge region of the binding site. The secondary amines with naphthalen-2-ylmethyl, 5-phenylthiophen-2-ylmethyl, and 1H-indol-2-ylmethyl (2 j) substituents exhibited the highest potency against class I HDACs: HDAC1 IC50 39-61 nm, HDAC2 IC50 260-690 nm, HDAC3 IC50 25-68 nm, and HDAC8 IC50 320-620 nm. The cytotoxicity of a representative set of secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors against HT-29, SH-SY5Y, and MCF-7 cancer cells correlated with their inhibition of HDAC1, 2, and 3 and was found to be similar to or better than that of suberoylanilide hydroxamic acid (SAHA). Compds. in this series increased the acetylation of histones H3 and H4 in a time-dependent manner. DMPK studies indicated that secondary amine 2 j is metabolically stable and has plasma and brain concns. >23- and >1.6-fold higher than the IC50 value for class I HDACs, resp. Overall, the secondary and tertiary N-substituted 7-aminoheptanoic acid hydroxyamide-based inhibitors exhibit excellent lead- and drug-like properties and therapeutic capacity for cancer applications.
- 303Taha, T. Y.; Aboukhatwa, S. M.; Knopp, R. C.; Ikegaki, N.; Abdelkarim, H.; Neerasa, J.; Lu, Y.; Neelarapu, R.; Hanigan, T. W.; Thatcher, G. R. J.; Petukhov, P. A. Design, synthesis, and biological evaluation of tetrahydroisoquinoline-based histone deacetylase 8 selective inhibitors. ACS Med. Chem. Lett. 2017, 8, 824– 829, DOI: 10.1021/acsmedchemlett.7b00126[ACS Full Text], [CAS], Google Scholar303https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2sXht1Cls7bJ&md5=5799a2ed9d2c772db5bc4355a102f814Design, Synthesis, and Biological Evaluation of Tetrahydroisoquinoline-Based Histone Deacetylase 8 Selective InhibitorsTaha, Taha Y.; Aboukhatwa, Shaimaa M.; Knopp, Rachel C.; Ikegaki, Naohiko; Abdelkarim, Hazem; Neerasa, Jayaprakash; Lu, Yunlong; Neelarapu, Raghupathi; Hanigan, Thomas W.; Thatcher, Gregory R. J.; Petukhov, Pavel A.ACS Medicinal Chemistry Letters (2017), 8 (8), 824-829CODEN: AMCLCT; ISSN:1948-5875. (American Chemical Society)Histone deacetylase 8 (HDAC8) is a promising drug target for multiple therapeutic applications. Here, we describe the modeling, design, synthesis, and biol. evaluation of a novel series of C1-substituted tetrahydroisoquinoline (TIQ)-based HDAC8 inhibitors. Minimization of entropic loss upon ligand binding and use of the unique HDAC8 "open" conformation of the binding site yielded a successful strategy for improvement of both HDAC8 potency and selectivity. The TIQ-based I and II exhibited the highest 82 and 55 nM HDAC8 potency and 330- and 135-fold selectivity over HDAC1, resp. Selectivity over other class I isoforms was comparable or better, whereas inhibition of HDAC6, a class II HDAC isoform, was below 50% at 10 μM. The cytotoxicity of I and II was evaluated in neuroblastoma cell lines, and II displayed concn.-dependent cytotoxicity similar to or better than that of PCI-34051. The selectivity of I and II was confirmed in SH-SY5Y cells as both did not increase the acetylation of histone H3 and α-tubulin. Discovery of the novel TIQ chemotype paves the way for the development of HDAC8 selective inhibitors for therapeutic applications.
- 304Chou, C. J.; Herman, D.; Gottesfeld, J. M. Pimelic diphenylamide 106 is a slow, tight-binding inhibitor of class I histone deacetylases. J. Biol. Chem. 2008, 283, 35402– 35409, DOI: 10.1074/jbc.M807045200[Crossref], [PubMed], [CAS], Google Scholar304https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhsVylsr3L&md5=ffcdd2b6a6884d7fa48076c9bf228011Pimelic Diphenylamide 106 Is a Slow, Tight-binding Inhibitor of Class I Histone DeacetylasesChou, C. James; Herman, David; Gottesfeld, Joel M.Journal of Biological Chemistry (2008), 283 (51), 35402-35409CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)Histone deacetylase (HDAC) inhibitors, including various benzamides and hydroxamates, are currently in clin. development for a broad range of human diseases, including cancer and neurodegenerative diseases. We recently reported the identification of a family of benzamide-type HDAC inhibitors that are relatively non-toxic compared with the hydroxamates. Members of this class of compds. have shown efficacy in cell-based and mouse models for the neurodegenerative diseases Friedreich ataxia and Huntington disease. Considerable differences in IC50 values for the various HDAC enzymes have been reported for many of the HDAC inhibitors, leading to confusion as to the HDAC isotype specificities of these compds. Here we show that a benzamide HDAC inhibitor, a pimelic diphenylamide (106), is a class I HDAC inhibitor, demonstrating no activity against class II HDACs. 106 Is a slow, tight-binding inhibitor of HDACs 1, 2, and 3, although inhibition for these enzymes occurs through different mechanisms. Inhibitor 106 also has preference toward HDAC3 with Ki of ∼14 nM, 15 times lower than the Ki for HDAC1. In comparison, the hydroxamate suberoylanilide hydroxamic acid does not discriminate between these enzymes and exhibits a fast-on/fast-off inhibitory mechanism. These observations may explain a paradox involving the relative activities of pimelic diphenylamides vs. hydroxamates as gene activators.
- 305Yao, Y.; Tu, Z.; Liao, C.; Wang, Z.; Li, S.; Yao, H.; Li, Z.; Jiang, S. Discovery of novel class i histone deacetylase inhibitors with promising in vitro and in vivo antitumor activities. J. Med. Chem. 2015, 58, 7672– 7680, DOI: 10.1021/acs.jmedchem.5b01044[ACS Full Text], [CAS], Google Scholar305https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXhsVCgurnI&md5=3069fbc43dc2cc5ead040bad2021cae3Discovery of Novel Class I Histone Deacetylase Inhibitors with Promising in Vitro and in Vivo Antitumor ActivitiesYao, Yiwu; Tu, Zhengchao; Liao, Chenzhong; Wang, Zhen; Li, Shang; Yao, Hequan; Li, Zheng; Jiang, ShengJournal of Medicinal Chemistry (2015), 58 (19), 7672-7680CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)A successful structure-based design of novel cyclic depsipeptides that selectively target class I HDAC isoforms is described. Compd. I [R = H] an IC50 of 2.78 nM for binding to the HDAC1 protein, and the prodrugs I [R = Me(CH2)6C(O)] and I [R = MeC(O)] also exhibit promising antiproliferative activities in the nanomolar range against various cancer cell lines. Compds. I [R = Me(CH2)6C(O)] and I [R = MeC(O)] show more than 20-fold selectivity toward human cancer cells over human normal cells in comparison with romidepsin (FK228), demonstrating low probability of toxic side effects. In addn., compd. I [R = MeC(O)] exhibits excellent in vivo anticancer activities in a human prostate carcinoma (Du145) xenograft model with no obsd. toxicity. Thus, prodrug I [R = MeC(O)] has therapeutic potential as a new class of anticancer agent for further clin. translation.
- 306Soumyanarayanan, U.; Ramanujulu, P. M.; Mustafa, N.; Haider, S.; Fang Nee, A. H.; Tong, J. X.; Tan, K. S. W.; Chng, W. J.; Dymock, B. W. Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitor. Eur. J. Med. Chem. 2019, 184, 111755, DOI: 10.1016/j.ejmech.2019.111755[Crossref], [PubMed], [CAS], Google Scholar306https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1MXhvF2gs7fP&md5=bb0b3d40a7ea91b92d9f12dccd922851Discovery of a potent histone deacetylase (HDAC) 3/6 selective dual inhibitorSoumyanarayanan, Uttara; Ramanujulu, Pondy Murugappan; Mustafa, Nurulhuda; Haider, Shozeb; Fang Nee, Adina Huey; Tong, Jie Xin; Tan, Kevin S. W.; Chng, Wee Joo; Dymock, Brian W.European Journal of Medicinal Chemistry (2019), 184 (), 111755CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)Herein, we report the discovery of a dual histone deacetylase inhibitor displaying a unique HDAC3/6 selectivity profile. An initial strategy to merge two epigenetic pharmacophores resulted in the discovery of potent HDAC6 inhibitors with selectivity over HDAC1. Screening in an HDAC panel revealed addnl. low nanomolar inhibition only against HDAC3. Low micromolar antiproliferative activities against two breast cancer and four hematol. cancer cell lines was supported by pharmacodynamic studies on a preferred mol., 24c, substantiating the HDAC inhibitory profile in cells. Apoptosis was identified as one of the main cell death pathways. Modeling studies of 24c against HDAC1,2,3 and 6 further provided insights on the orientation of specific residues relevant to compd. potency, explaining the obsd. HDAC3/6 selectivity. A subset of the compds. also exhibited good antimalarial activities, particularly against the chloroquine-resistant strain K1 of P.falciparum. In vitro studies revealed a favorable DMPK profile warranting further investigation of the therapeutic potential of these compds.
- 307Adhikari, N.; Amin, S. A.; Trivedi, P.; Jha, T.; Ghosh, B. HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approaches. Eur. J. Med. Chem. 2018, 157, 1127– 1142, DOI: 10.1016/j.ejmech.2018.08.081[Crossref], [PubMed], [CAS], Google Scholar307https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXhs1emtrzO&md5=2e916b713c3d7442ea082d0688ec3da0HDAC3 is a potential validated target for cancer: An overview on the benzamide-based selective HDAC3 inhibitors through comparative SAR/QSAR/QAAR approachesAdhikari, Nilanjan; Amin, Sk. Abdul; Trivedi, Prakruti; Jha, Tarun; Ghosh, BalaramEuropean Journal of Medicinal Chemistry (2018), 157 (), 1127-1142CODEN: EJMCA5; ISSN:0223-5234. (Elsevier Masson SAS)A review. Deacetylation of histones by histone deacetylase 3 (HDAC3) is involved in apoptosis, cellular progression and DNA damage. Due to the overexpression of HDAC3 in a variety of cancers, it is implicated to be a crucial validated target for cancer. Therefore, HDAC3 selective inhibitors have roles to play in combating these cancers. Nowadays, compds. comprising benzamide functionality as zinc binding group (ZBG) have been emerged out to be highly effective and selective HDAC3 inhibitors. In this article, QSAR and QAAR studies have been conducted on diverse benzamide-derived HDAC3 inhibitors as the first initiative to explore the designing strategies of higher active and selective HDAC3 inhibitors over HDAC1 and HDAC2. QSAR models reveal that mol. size and shape along with the steric effect should have to be optimized to achieve higher HDAC3 inhibition. QAAR models reflect that modification/substitution at the benzamide scaffold should be optimized in such a way so that these mols. possess lower steric bulk along with nonpolar features for achieving higher HDAC3 selectivity over HDAC1 and HDAC2. However, the importance of spiro hydrophobic cap group, as well as electron withdrawing fluorine group at the benzamide scaffold, should be well-accounted for retaining higher HDAC3 selectivity over HDAC1. Moreover, less polar and less hydrophobic benzamides are preferred for HDAC3 selectivity over HDAC2. This detailed structural exploration will surely unveil a new vista of designing highly potent and selective benzamide-based HDAC3 inhibitors that may be a crucial weapon to battle against a variety of cancers.
- 308Amin, S. A.; Adhikari, N.; Jha, T.; Ghosh, B. Designing potential HDAC3 inhibitors to improve memory and learning. J. Biomol. Struct. Dyn. 2019, 37, 2133– 2142, DOI: 10.1080/07391102.2018.1477625[Crossref], [PubMed], [CAS], Google Scholar308https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC1cXisFWru7rK&md5=35290ed8294866346db72077fdbde266Designing potential HDAC3 inhibitors to improve memory and learningAmin, Sk. Abdul; Adhikari, Nilanjan; Jha, Tarun; Ghosh, BalaramJournal of Biomolecular Structure and Dynamics (2019), 37 (8), 2133-2142CODEN: JBSDD6; ISSN:0739-1102. (Taylor & Francis Ltd.)The work presented here explores the structural and physicochem. features important for benzamide-based HDAC3 inhibitors to get an idea about the design aspect of potential inhibitors. A no. of mol. modeling studies (3D-QSAR CoMFA and CoMSIA, Bayesian classification modeling) were performed on 113 diverse set of benzamide-based HDAC3 inhibitors. All these models developed are statistically reliable and correlate the SAR observations. Electron withdrawing substitution is favorable but the bulky hydrophobic group at the cap region reduces HDAC3 inhibition. Hydrophobicity and steric feature of the aryl linker function favor the activity. Aryl group substituted benzamide functionality is not favorable for HDAC3 inhibition. The amide function of the benzamide moiety is essential for Zn2+ chelation and the carboxylic acid function may serve as a hydrogen bond acceptor (HBA) feature. Moreover, electron withdrawing substituent at the benzamide moiety influences activity whereas steric and hydrophobic substituents reduce HDAC3 inhibition. Overall, this study may provide a valuable insight on the design of better active HDAC3 inhibitors in future.